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S S, Amirtham U, Gopal C, Arjun R, Jacob L. Prognostic Implications of Concurrent Ductal Carcinoma In Situ in Invasive Breast Cancer: an Observational Nested Cohort Study from a Regional Cancer Center in India. Indian J Surg Oncol 2025; 16:508-515. [PMID: 40337017 PMCID: PMC12052639 DOI: 10.1007/s13193-023-01853-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 11/20/2023] [Indexed: 05/09/2025] Open
Abstract
Ductal Carcinoma In Situ (DCIS) is not an obligate precursor to invasive breast cancer and can exhibit variations in clinical presentation, genetics, biomarkers, and morphological features. There are contrasting views in literature with regard to prognostic significance of DCIS component in invasive cancer. Hence, this study aimed to evaluate how the co-occurrence of DCIS affects the prognosis of people with invasive breast cancer (IBC). A retrospective nested cohort observational study of patients with invasive breast cancer with and without DCIS component was conducted to compare the types of metastases developed on the subsequent follow-up, treatment details, event free survival and other histopathological parameters. There was a significant difference (p = 0.014) in the mean age at diagnosis between patients of IBC with concurrent DCIS (45 ± 11.18 years) and those who had IBC alone (53.24 ± 10.45 years). Invasive cancer with concurrent DCIS component tends to be more common in patients less than 50 years age group (p = 0.03). Majority (75.56%) of the patients were in post-menopausal stage. Patients with concurrent DCIS had higher frequencies of tumors of T1/ T2 stages and zero nodal status. Higher frequencies of local recurrence and visceral metastases were observed in patients with DCIS component compared to patients with IBC alone. Majority had received complete treatment. Longer event free survival was noted in patients with DCIS component compared to those with IBC alone. Our study demonstrated significant association of concurrent DCIS component with mean age at diagnosis in patients with invasive breast cancer. Although a trend towards favorable tumor profile was observed, larger prospective studies are required to enhance the statistical power of our findings. In view of its impact on clinical outcome, it is important to risk stratify invasive breast cancer based on the features of concurrent DCIS component.
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Affiliation(s)
- Shanthala S
- Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore City, Karnataka India
| | - Usha Amirtham
- Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore City, Karnataka India
| | - Champaka Gopal
- Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore City, Karnataka India
| | - Ravi Arjun
- Department of Surgical Oncology, Kidwai Memorial Institute of Oncology, Bangalore City, Karnataka India
| | - Linu Jacob
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore City, Karnataka India
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Behbod F, Chen JH, Thompson A. Human Ductal Carcinoma In Situ: Advances and Future Perspectives. Cold Spring Harb Perspect Med 2023; 13:a041319. [PMID: 36781223 PMCID: PMC10547390 DOI: 10.1101/cshperspect.a041319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
Due to widespread adoption of screening mammography, there has been a significant increase in new diagnoses of ductal carcinoma in situ (DCIS). However, DCIS outcomes remain unclear. A large fraction of human DCIS (>50%) may not need the multimodality treatment options currently offered to all DCIS patients. More importantly, while we may be overtreating many, we cannot identify those most at risk of invasion or metastasis following a DCIS diagnosis. This review summarizes the studies that have furthered our understanding of DCIS pathology and mechanisms of invasive progression by using advanced technologies including spatial genomics, transcriptomics, and multiplex proteomics. This review also highlights a need for rethinking DCIS with a more focused view on epithelial states and programs and their cross talk with the microenvironment.
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Affiliation(s)
- Fariba Behbod
- Department of Pathology and Laboratory Medicine, MS 3045, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Jennifer H Chen
- Michael E. Debakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA
| | - Alastair Thompson
- Section of Breast Surgery, Baylor College of Medicine, Co-Director, Lester and Sue Smith Breast Center, Dan L Duncan Comprehensive Cancer Center, Houston, Texas 77030, USA
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3
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Zhang J, Lin H, Hou L, Xiao H, Gong X, Guo X, Cao X, Liu Z. Exploration of the breast ductal carcinoma in situ signature and its prognostic implications. Cancer Med 2022; 12:3758-3772. [PMID: 35880695 PMCID: PMC9939111 DOI: 10.1002/cam4.5071] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 06/06/2022] [Accepted: 07/03/2022] [Indexed: 11/06/2022] Open
Abstract
Following the implementation of breast screening programs, the occurrence of ductal carcinoma in situ (DCIS) as an early type of neoplasia has increased. Although the prognosis is promising, 20%-50% of DCIS patients will progress to invasive ductal carcinoma (IDC) if not treated. It is essential to look for promising biomarkers for predicting DCIS prognosis. The Gene Expression Omnibus (GEO) database was used to explore the expression of genes that differed between DCIS and normal tissue in this investigation. Enrichment analysis was performed to characterize the biological role and intrinsic process pathway. The Cancer Genome Atlas Breast Cancer Dataset was used to categorize the hub genes, and the results were confirmed using the Cytoscape plugin CytoHubba and MCODE. The prognostic ability of the core gene signature was determined through time-dependent receiver operating characteristic (ROC), Kaplan-Meier survival curve, Oncomine databases, and UALCAN databases. In addition, the prognostic value of core genes was verified in proliferation assays. We identified 217 common differentially expressed genes (DEGs) in the present study, with 101 upregulated and 138 downregulated genes. The top genes were obtained from the PPI network (protein-protein interaction). A unique six-gene signature (containing GAPDH, CDH2, BIRC5, NEK2, IDH2, and MELK) was developed for DCIS prognostic prediction. Centered on the Cancer Genome Atlas (TCGA) cohort, the ROC curve showed strong results in prognosis prediction. The six core gene signatures is often overexpressed in DCIS, with a weak prognosis. Furthermore, when breast cancer cells are transfected with small interfering RNAs, downregulation of core gene expression substantially inhibits cell proliferation, revealing a high potential for employing core genes in DCIS prognosis. In conclusion, the current investigation verified the six core genes signatures for prospective DCIS biomarkers, which may aid clinical decision-making for individual care.
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Affiliation(s)
- Jiao Zhang
- Department of Breast Disease, Henan Breast Cancer CenterAffiliated Cancer Hospital of Zhengzhou University & Henan Cancer HospitalZhengzhouChina
| | - Hui Lin
- The First Department of Breast CancerTianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of EducationTianjinChina,Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical UniversityTaizhouChina
| | - Lei Hou
- Department of Breast Disease, Henan Breast Cancer CenterAffiliated Cancer Hospital of Zhengzhou University & Henan Cancer HospitalZhengzhouChina
| | - Hui Xiao
- Department of Breast Disease, Henan Breast Cancer CenterAffiliated Cancer Hospital of Zhengzhou University & Henan Cancer HospitalZhengzhouChina
| | - Xilong Gong
- Department of Breast Disease, Henan Breast Cancer CenterAffiliated Cancer Hospital of Zhengzhou University & Henan Cancer HospitalZhengzhouChina
| | - Xuhui Guo
- Department of Breast Disease, Henan Breast Cancer CenterAffiliated Cancer Hospital of Zhengzhou University & Henan Cancer HospitalZhengzhouChina
| | - Xuchen Cao
- The First Department of Breast CancerTianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of EducationTianjinChina
| | - Zhenzhen Liu
- Department of Breast Disease, Henan Breast Cancer CenterAffiliated Cancer Hospital of Zhengzhou University & Henan Cancer HospitalZhengzhouChina
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Xu H, Lien T, Bergholtz H, Fleischer T, Djerroudi L, Vincent-Salomon A, Sørlie T, Aittokallio T. Multi-Omics Marker Analysis Enables Early Prediction of Breast Tumor Progression. Front Genet 2021; 12:670749. [PMID: 34149812 PMCID: PMC8209521 DOI: 10.3389/fgene.2021.670749] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/26/2021] [Indexed: 12/13/2022] Open
Abstract
Ductal carcinoma in situ (DCIS) is a preinvasive form of breast cancer with a highly variable potential of becoming invasive and affecting mortality of the patients. Due to the lack of accurate markers of disease progression, many women with detected DCIS are currently overtreated. To distinguish those DCIS cases who are likely to require therapy from those who should be left untreated, there is a need for robust and predictive biomarkers extracted from molecular or genetic profiles. We developed a supervised machine learning approach that implements multi-omics feature selection and model regularization for the identification of biomarker combinations that could be used to distinguish low-risk DCIS lesions from those with a higher likelihood of progression. To investigate the genetic heterogeneity of disease progression, we applied this approach to 40 pure DCIS and 259 invasive breast cancer (IBC) samples profiled with genome-wide transcriptomics, DNA methylation, and DNA copy number variation. Feature selection using the multi-omics Lasso-regularized algorithm identified both known genes involved in breast cancer development, as well as novel markers for early detection. Even though the gene expression-based model features led to the highest classification accuracy alone, methylation data provided a complementary source of features and improved especially the sensitivity of correctly classifying DCIS cases. We also identified a number of repeatedly misclassified DCIS cases when using either the expression or methylation markers. A small panel of 10 gene markers was able to distinguish DCIS and IBC cases with high accuracy in nested cross-validation (AU-ROC = 0.99). The marker panel was not specific to any of the established breast cancer subtypes, suggesting that the 10-gene signature may provide a subtype-agnostic and cost-effective approach for breast cancer detection and patient stratification. We further confirmed high accuracy of the 10-gene signature in an external validation cohort (AU-ROC = 0.95), profiled using distinct transcriptomic assay, hence demonstrating robustness of the risk signature.
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Affiliation(s)
- Haifeng Xu
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Oslo Centre for Biostatistics and Epidemiology (OCBE), University of Oslo, Oslo, Norway
| | - Tonje Lien
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Helga Bergholtz
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Thomas Fleischer
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Lounes Djerroudi
- Institut Curie, Ensemble Hospitalier, Pôle de Médecine Diagnostique et Théranostique, Département de Pathologie, Paris, France
| | - Anne Vincent-Salomon
- Institut Curie, Ensemble Hospitalier, Pôle de Médecine Diagnostique et Théranostique, Département de Pathologie, Paris, France
| | - Therese Sørlie
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Tero Aittokallio
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Oslo Centre for Biostatistics and Epidemiology (OCBE), University of Oslo, Oslo, Norway.,Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
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Şumnu Ş, Mehtap Ö, Mersin S, Toptaş T, Görür G, Gedük A, Ünal S, Polat MG, Aygün K, Yenihayat EM, Albayrak H, Uluköylü Mengüç M, Tarkun P, Hacıhanifioğlu A. Serum calprotectin (S100A8/A9) levels as a new potential biomarker of treatment response in Hodgkin lymphoma. Int J Lab Hematol 2021; 43:638-644. [PMID: 33904653 DOI: 10.1111/ijlh.13559] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 04/04/2021] [Accepted: 04/06/2021] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Hodgkin lymphoma (HL) is unusual among malignancies, with inflammation playing such a prominent role in its pathogenesis. S100A8/A9 (calprotectin) is a heterodimeric protein, which has a role in the inflammatory response and oncogenesis. In this study in HL patients, the correlation between serum S100A8/A9 levels and treatment responses was investigated along with whether this marker is correlated with other inflammatory markers. MATERIALS AND METHODS Thirty-three HL patients and 20 healthy volunteers were included. Demographic and clinical characteristics were recorded. Calprotectin levels were measured with Human S100A8/A9 Heterodimer Quantikine ELISA kit. Calprotectin levels were measured twice in patients, before and after treatment, and once in the control group. Treatment responses were evaluated with positron emission tomography-computed tomography (PET-CT). RESULTS The mean age of patients was 44.3 ± 18.1 (66.3% male). The median (IQR) values of S100A8/A9 before and after treatment in the patient group were 4.98 (2.6-7.8) and 1.87 (1.1-4.8)µg/mL. Median (IQR) S100A8/A9 concentration in the control group was 1.41 (0.98-2.73)µg/mL. In patients, pretreatment values were significantly higher than in controls (P < .001). However, median values of patients after treatment and controls were similar. Patient median S100A8/A9 levels were significantly lower post-treatment compared with pretreatment values (P = .001). When inflammatory markers were examined within groups, no relationship was found between markers. In ROC analysis, a S100A8/A9 cutoff value of ≥3.31µg/mL accurately discriminated end-of-treatment PET positivity (AUC = 0.78; 95% CI 0.58-0.98; accuracy = 76.2%). CONCLUSION S100A8/A9 may be a potential biomarker for treatment response in HL independent of inflammation. This is the first study to investigate and show this finding. However, further large-scale studies are still required.
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Affiliation(s)
- Şeyma Şumnu
- Department of Hematology, Medical Faculty, University of Kocaeli, Kocaeli, Turkey
| | - Özgür Mehtap
- Department of Hematology, Medical Faculty, University of Kocaeli, Kocaeli, Turkey
| | - Sinan Mersin
- Department of Hematology, Medical Faculty, University of Kocaeli, Kocaeli, Turkey
| | - Tayfur Toptaş
- Department of Hematology, Marmara University Hospital, Istanbul, Turkey
| | - Gözde Görür
- Department of Nuclear Medicine, Medical Faculty, University of Kocaeli, Kocaeli, Turkey
| | - Ayfer Gedük
- Department of Hematology, Medical Faculty, University of Kocaeli, Kocaeli, Turkey
| | - Serkan Ünal
- Department of Hematology, Medical Faculty, University of Kocaeli, Kocaeli, Turkey
| | - Merve Gökçen Polat
- Department of Hematology, Medical Faculty, University of Kocaeli, Kocaeli, Turkey
| | - Kemal Aygün
- Department of Hematology, Medical Faculty, University of Kocaeli, Kocaeli, Turkey
| | - Emel Merve Yenihayat
- Department of Hematology, Medical Faculty, University of Kocaeli, Kocaeli, Turkey
| | - Hayrunnisa Albayrak
- Department of Hematology, Medical Faculty, University of Kocaeli, Kocaeli, Turkey
| | - Meral Uluköylü Mengüç
- Department of Hematology, Medical Faculty, Bolu İzzet Baysal University, Bolu, Turkey
| | - Pınar Tarkun
- Department of Hematology, Medical Faculty, University of Kocaeli, Kocaeli, Turkey
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Thike AA, Chen X, Koh VCY, Binte Md Nasir ND, Yeong JPS, Bay BH, Tan PH. Higher densities of tumour-infiltrating lymphocytes and CD4 + T cells predict recurrence and progression of ductal carcinoma in situ of the breast. Histopathology 2021; 76:852-864. [PMID: 31883279 DOI: 10.1111/his.14055] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 12/14/2019] [Accepted: 12/24/2019] [Indexed: 12/13/2022]
Abstract
AIMS Host immunity influences cancer progression and therapeutic response. We investigated the potential of tumour-infiltrating lymphocytes (TILs) around ductal carcinoma in situ (DCIS) in predicting recurrence and progression. METHODS AND RESULTS CD4, CD8, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression in DCIS from 198 patients was determined by immunohistochemistry. We correlated disease-free survival (DFS), clinicopathological parameters and biomarker expression with TIL density and CD4/CD8 ratio. High TIL density was associated with high nuclear grade (P < 0.001), DCIS PD-L1 expression (P = 0.008), TIL PD-L1 expression (P < 0.001), oestrogen (ER) negativity (P < 0.001), progesterone (PR) negativity (P < 0.001), human epidermal growth factor receptor 2 (HER2) positivity (P = 0.002) and triple negativity (P = 0.001). TIL PD-L1 expression was associated with triple-negative DCIS (P = 0.028). TIL density was associated with molecular subtypes (P < 0.001). High CD4+ T cell density was associated with high nuclear grade (P = 0.001), microinvasion (P = 0.037), ER negativity (P < 0.001), PR negativity (P = 0.001), HER2 positivity (P = 0.004), triple negativity (P = 0.023) and PD-L1 expression in TILs (P < 0.011). High CD4/CD8 ratio was associated with PD-L1 expression in DCIS (P = 0.035) and TILs (P < 0.001). DCIS with higher TIL density disclosed worse DFS (P = 0.012) and was affirmed with multivariate analysis [95% confidence interval (CI) = 1.109-2.554, hazard ratio (HR) = 1.683, P = 0.014]. Poorer DFS for ipsilateral invasive recurrence was found for DCIS with higher CD4+ T cell density (P = 0.006) or CD4/CD8 ratio (P = 0.02), confirmed by multivariate analysis for the former (95% CI = 1.369-10.196, HR = 3.736, P = 0.01) and latter (95% CI = 1.311-7.935, HR = 3.225, P = 0.011). CONCLUSION DCIS with higher TIL density was associated with poorer prognostic parameters and predicted recurrence, while both CD4+ T cell density and CD4/CD8 ratio were associated with both recurrence and ipsilateral invasive recurrence.
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Affiliation(s)
- Aye Aye Thike
- Department of Anatomical Pathology, Singapore General Hospital, Singapore.,Duke-NUS Medical School, Singapore
| | - Xiaoyang Chen
- Department of Anatomical Pathology, Singapore General Hospital, Singapore.,Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | | | - Joe P S Yeong
- Department of Anatomical Pathology, Singapore General Hospital, Singapore.,Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Boon Huat Bay
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Puay Hoon Tan
- Department of Anatomical Pathology, Singapore General Hospital, Singapore.,Duke-NUS Medical School, Singapore.,Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Division of Pathology, Singapore General Hospital, Singapore
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Van Bockstal MR, Berlière M, Duhoux FP, Galant C. Interobserver Variability in Ductal Carcinoma In Situ of the Breast. Am J Clin Pathol 2020; 154:596-609. [PMID: 32566938 DOI: 10.1093/ajcp/aqaa077] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES Since most patients with ductal carcinoma in situ (DCIS) of the breast are treated upon diagnosis, evidence on its natural progression to invasive carcinoma is limited. It is estimated that around half of the screen-detected DCIS lesions would have remained indolent if they had never been detected. Many patients with DCIS are therefore probably overtreated. Four ongoing randomized noninferiority trials explore active surveillance as a treatment option. Eligibility for these trials is mainly based on histopathologic features. Hence, the call for reproducible histopathologic assessment has never sounded louder. METHODS Here, the available classification systems for DCIS are discussed in depth. RESULTS This comprehensive review illustrates that histopathologic evaluation of DCIS is characterized by significant interobserver variability. Future digitalization of pathology, combined with development of deep learning algorithms or so-called artificial intelligence, may be an innovative solution to tackle this problem. However, implementation of digital pathology is not within reach for each laboratory worldwide. An alternative classification system could reduce the disagreement among histopathologists who use "conventional" light microscopy: the introduction of dichotomous histopathologic assessment is likely to increase interobserver concordance. CONCLUSIONS Reproducible histopathologic assessment is a prerequisite for robust risk stratification and adequate clinical decision-making. Two-tier histopathologic assessment might enhance the quality of care.
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Affiliation(s)
- Mieke R Van Bockstal
- Department of Pathology, Brussels, Belgium
- Breast Clinic, Brussels, Belgium
- Department of Medical Oncology, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Martine Berlière
- Department of Medical Oncology, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Brussels, Belgium
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium
| | - Francois P Duhoux
- Department of Medical Oncology, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Brussels, Belgium
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium
- Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Christine Galant
- Department of Pathology, Brussels, Belgium
- Department of Medical Oncology, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Brussels, Belgium
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Wu M, Zhao H. Analysis of key genes and pathways in breast ductal carcinoma in situ. Oncol Lett 2020; 20:217. [PMID: 32963623 PMCID: PMC7491034 DOI: 10.3892/ol.2020.12080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 09/17/2019] [Indexed: 12/12/2022] Open
Abstract
Breast cancer (BC) remains the most common cancer in females. Therefore, the present study aimed to identify key genes involved in the carcinogenesis of BC and to explore their prognostic values by integrating bioinformatics tools. The gene expression profiles of 46 ductal carcinoma in situ (DCIS) and three normal breast tissues from the GSE59248 dataset were downloaded. Differentially expressed genes (DEGs) were subsequently identified using the online tool GEO2R and a functional enrichment analysis was performed. In addition, a protein-protein interaction (PPI) network was constructed and the top eight hub genes were identified. The prognostic values of the hub genes were further investigated. A total of 316 DEGs, including 32 upregulated and 284 downregulated genes, were identified. Furthermore, eight hub genes, including lipase E hormone sensitive type, patatin like phospholipase domain containing 2, adiponectin C1Q and collagen domain containing (ADIPOQ), peroxisome proliferator activated receptor γ (PPARG), fatty acid binding protein 4 (FABP4), diacylglycerol O-acyltransferase 2, lipoprotein lipase (LPL) and leptin (LEP), were identified from the PPI network. The downregulated expression of ADIPOQ, PPARG, FABP4, LPL and LEP was significantly associated with poor overall survival in patients with DCIS. Therefore, these genes may serve as potential biomarkers for prognosis prediction. However, further investigation is required to validate the results obtained in the present study.
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Affiliation(s)
- Min Wu
- Department of General Surgery, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Hongmei Zhao
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, P.R. China
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Interobserver variability in upfront dichotomous histopathological assessment of ductal carcinoma in situ of the breast: the DCISion study. Mod Pathol 2020; 33:354-366. [PMID: 31534203 PMCID: PMC7983551 DOI: 10.1038/s41379-019-0367-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 09/01/2019] [Accepted: 09/02/2019] [Indexed: 12/11/2022]
Abstract
Histopathological assessment of ductal carcinoma in situ, a nonobligate precursor of invasive breast cancer, is characterized by considerable interobserver variability. Previously, post hoc dichotomization of multicategorical variables was used to determine the "ideal" cutoffs for dichotomous assessment. The present international multicenter study evaluated interobserver variability among 39 pathologists who performed upfront dichotomous evaluation of 149 consecutive ductal carcinomas in situ. All pathologists independently assessed nuclear atypia, necrosis, solid ductal carcinoma in situ architecture, calcifications, stromal architecture, and lobular cancerization in one digital slide per lesion. Stromal inflammation was assessed semiquantitatively. Tumor-infiltrating lymphocytes were quantified as percentages and dichotomously assessed with a cutoff at 50%. Krippendorff's alpha (KA), Cohen's kappa and intraclass correlation coefficient were calculated for the appropriate variables. Lobular cancerization (KA = 0.396), nuclear atypia (KA = 0.422), and stromal architecture (KA = 0.450) showed the highest interobserver variability. Stromal inflammation (KA = 0.564), dichotomously assessed tumor-infiltrating lymphocytes (KA = 0.520), and comedonecrosis (KA = 0.539) showed slightly lower interobserver disagreement. Solid ductal carcinoma in situ architecture (KA = 0.602) and calcifications (KA = 0.676) presented with the lowest interobserver variability. Semiquantitative assessment of stromal inflammation resulted in a slightly higher interobserver concordance than upfront dichotomous tumor-infiltrating lymphocytes assessment (KA = 0.564 versus KA = 0.520). High stromal inflammation corresponded best with dichotomously assessed tumor-infiltrating lymphocytes when the cutoff was set at 10% (kappa = 0.881). Nevertheless, a post hoc tumor-infiltrating lymphocytes cutoff set at 20% resulted in the highest interobserver agreement (KA = 0.669). Despite upfront dichotomous evaluation, the interobserver variability remains considerable and is at most acceptable, although it varies among the different histopathological features. Future studies should investigate its impact on ductal carcinoma in situ prognostication. Forthcoming machine learning algorithms may be useful to tackle this substantial diagnostic challenge.
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10
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I. Mohammed S, Utturkar S, Lee M, Yang HH, Cui Z, Atallah Lanman N, Zhang G, Ramos Cardona XE, Mittal SK, Miller MA. Ductal Carcinoma In Situ Progression in Dog Model of Breast Cancer. Cancers (Basel) 2020; 12:cancers12020418. [PMID: 32053966 PMCID: PMC7072653 DOI: 10.3390/cancers12020418] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/25/2020] [Accepted: 02/06/2020] [Indexed: 12/12/2022] Open
Abstract
The mechanisms that drive ductal carcinoma in situ (DCIS) progression to invasive cancer are not clear. Studying DCIS progression in humans is challenging and not ethical, thus necessitating the characterization of an animal model that faithfully resembles human disease. We have characterized a canine model of spontaneous mammary DCIS and invasive cancer that shares histologic, molecular, and diagnostic imaging characteristics with DCIS and invasive cancer in women. The purpose of the study was to identify markers and altered signaling pathways that lead to invasive cancer and shed light on early molecular events in breast cancer progression and development. Transcriptomic studies along the continuum of cancer progression in the mammary gland from healthy, through atypical ductal hyperplasia (ADH), DCIS, and invasive carcinoma were performed using the canine model. Gene expression profiles of preinvasive DCIS lesions closely resemble those of invasive carcinoma. However, certain genes, such as SFRP2, FZD2, STK31, and LALBA, were over-expressed in DCIS compared to invasive cancer. The over-representation of myoepithelial markers, epithelial-mesenchymal transition (EMT), canonical Wnt signaling components, and other pathways induced by Wnt family members distinguishes DCIS from invasive. The information gained may help in stratifying DCIS as well as identify actionable targets for primary and tertiary prevention or targeted therapy.
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Affiliation(s)
- Sulma I. Mohammed
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA; (Z.C.); (N.A.L.); (G.Z.); (X.E.R.C.); (S.K.M.); (M.A.M.)
- Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA;
- Correspondence: ; Tel.: +1-765-494-9948; Fax: +1-765-494-9830
| | - Sagar Utturkar
- Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA;
| | - Maxwell Lee
- High Dimension Data Analysis Group, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20852, USA; (M.L.); (H.H.Y.)
| | - Howard H. Yang
- High Dimension Data Analysis Group, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20852, USA; (M.L.); (H.H.Y.)
| | - Zhibin Cui
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA; (Z.C.); (N.A.L.); (G.Z.); (X.E.R.C.); (S.K.M.); (M.A.M.)
| | - Nadia Atallah Lanman
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA; (Z.C.); (N.A.L.); (G.Z.); (X.E.R.C.); (S.K.M.); (M.A.M.)
- Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA;
| | - GuangJun Zhang
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA; (Z.C.); (N.A.L.); (G.Z.); (X.E.R.C.); (S.K.M.); (M.A.M.)
- Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA;
| | - Xavier E. Ramos Cardona
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA; (Z.C.); (N.A.L.); (G.Z.); (X.E.R.C.); (S.K.M.); (M.A.M.)
| | - Suresh K. Mittal
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA; (Z.C.); (N.A.L.); (G.Z.); (X.E.R.C.); (S.K.M.); (M.A.M.)
- Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA;
| | - Margaret A. Miller
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA; (Z.C.); (N.A.L.); (G.Z.); (X.E.R.C.); (S.K.M.); (M.A.M.)
- Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA;
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11
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Yoosuf N, Navarro JF, Salmén F, Ståhl PL, Daub CO. Identification and transfer of spatial transcriptomics signatures for cancer diagnosis. Breast Cancer Res 2020; 22:6. [PMID: 31931856 PMCID: PMC6958738 DOI: 10.1186/s13058-019-1242-9] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 12/27/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Distinguishing ductal carcinoma in situ (DCIS) from invasive ductal carcinoma (IDC) regions in clinical biopsies constitutes a diagnostic challenge. Spatial transcriptomics (ST) is an in situ capturing method, which allows quantification and visualization of transcriptomes in individual tissue sections. In the past, studies have shown that breast cancer samples can be used to study their transcriptomes with spatial resolution in individual tissue sections. Previously, supervised machine learning methods were used in clinical studies to predict the clinical outcomes for cancer types. METHODS We used four publicly available ST breast cancer datasets from breast tissue sections annotated by pathologists as non-malignant, DCIS, or IDC. We trained and tested a machine learning method (support vector machine) based on the expert annotation as well as based on automatic selection of cell types by their transcriptome profiles. RESULTS We identified expression signatures for expert annotated regions (non-malignant, DCIS, and IDC) and build machine learning models. Classification results for 798 expression signature transcripts showed high coincidence with the expert pathologist annotation for DCIS (100%) and IDC (96%). Extending our analysis to include all 25,179 expressed transcripts resulted in an accuracy of 99% for DCIS and 98% for IDC. Further, classification based on an automatically identified expression signature covering all ST spots of tissue sections resulted in prediction accuracy of 95% for DCIS and 91% for IDC. CONCLUSIONS This concept study suggest that the ST signatures learned from expert selected breast cancer tissue sections can be used to identify breast cancer regions in whole tissue sections including regions not trained on. Furthermore, the identified expression signatures can classify cancer regions in tissue sections not used for training with high accuracy. Expert-generated but even automatically generated cancer signatures from ST data might be able to classify breast cancer regions and provide clinical decision support for pathologists in the future.
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Affiliation(s)
- Niyaz Yoosuf
- Department of Biosciences and Nutrition, Karolinska Institutet, 141 83, Huddinge, Sweden. .,Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden.
| | - José Fernández Navarro
- Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Fredrik Salmén
- Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden.,Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, Cancer Genomics Netherlands, Utrecht, the Netherlands
| | - Patrik L Ståhl
- Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Carsten O Daub
- Department of Biosciences and Nutrition, Karolinska Institutet, 141 83, Huddinge, Sweden.
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12
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Higher density of stromal M2 macrophages in breast ductal carcinoma in situ predicts recurrence. Virchows Arch 2020; 476:825-833. [PMID: 31897820 DOI: 10.1007/s00428-019-02735-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 12/12/2019] [Accepted: 12/18/2019] [Indexed: 10/25/2022]
Abstract
Immune response can affect tumour progression and treatment outcome. This study investigated the potential of stromal macrophages around ductal carcinoma in situ (DCIS) in predicting recurrence and progression. CD68 and CD163 expression of macrophages in DCIS from 198 patients was determined by immunohistochemistry. Disease free survival (DFS), clinicopathological parameters and biomarker expression were correlated with the densities of both CD68+ and CD163+ macrophages. High CD68+ macrophage density was associated with high nuclear grade (p < 0.001), oestrogen receptor (ER) negativity (p = 0.029), progesterone receptor (PR) negativity (p = 0.008) and human epidermal growth factor receptor 2 (HER2) positivity (p < 0.001). High CD163+ macrophage density was associated with high nuclear grade (p = 0.003), microinvasion (p = 0.01), ER negativity (p < 0.001), PR negativity (p = 0.001), HER2 positivity (p = 0.001) and triple negativity (p = 0.022). DCIS with higher CD68+ macrophage density disclosed significantly worse DFS for ipsilateral invasive recurrence (p = 0.004) and is affirmed by multivariate Cox regression analysis (95% CI 1.126-5.102, HR = 2.397, p = 0.023). DCIS with higher CD163+ macrophage density showed significantly worse DFS for both recurrence (p = 0.001) and ipsilateral invasive recurrence (p = 0.001). These findings, for CD163+ macrophage density, were affirmed by multivariate Cox regression analysis respectively for both recurrence (95% CI 1.210-2.293, HR = 1.880, p = 0.005) and ipsilateral invasive recurrence (95% CI 1.122-5.176, HR = 2.410, p = 0.024). This study demonstrated that DCIS with higher macrophage density was associated with poorer prognostic parameters, while DCIS with higher CD163+ macrophage density predicted both recurrence and ipsilateral invasive recurrence.
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13
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Grading Ductal Carcinoma In Situ (DCIS) of the Breast - What's Wrong with It? Pathol Oncol Res 2019; 26:665-671. [PMID: 31776839 PMCID: PMC7242244 DOI: 10.1007/s12253-019-00760-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 10/01/2019] [Indexed: 12/31/2022]
Abstract
Ductal carcinoma in situ of the breast is a non-obligate precursor of invasive breast cancer, and at its lower risk end might not need treatment, a hypothesis tested in several currently running randomized clinical trials. This review describes the heterogeneity of grading ductal carcinoma in situ (DCIS). First it considers differences between low and high grade DCIS, and then it looks at several grading schemes and highlights how different these are, not only in the features considered for defining a given grade but also in their wording of a given variable seen in the grade in question. Rather than being fully comprehensive, the review aims to illustrate the inconsistencies. Reproducibility studies on grading mostly suggestive of moderate agreement on DCIS differentiation are also illustrated. The need for a well structured, more uniform and widely accepted language for grading DCIS is urged to avoid misunderstanding based misclassifications and improper treatment selection.
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14
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Tot T, Gere M, Hofmeyer S, Bauer A, Pellas U. The clinical value of detecting microcalcifications on a mammogram. Semin Cancer Biol 2019; 72:165-174. [PMID: 31733292 DOI: 10.1016/j.semcancer.2019.10.024] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 10/30/2019] [Indexed: 12/22/2022]
Abstract
Many breast lesions are associated with microcalcifications that are detectable by mammography. In most cases, radiologists are able to distinguish calcifications usually associated with benign diseases from those associated with malignancy. In addition to their value in the early detection of breast carcinoma and accurate radiological diagnosis, the presence of microcalcifications often affects the extent of surgical intervention. Certain types of microcalcifications are associated with negative genetic and molecular characteristics of the tumor and unfavorable prognosis. Microcalcifications localized in the larger ducts (duct-centric, casting-type microcalcifications) represent an independent negative prognostic marker compared to lesions containing other types of microcalcifications and to non-calcified lesions. In this review, we summarize the theoretical and methodological background for understanding the clinical impact and discuss the diagnostic and prognostic value of microcalcifications detected in the breast by mammography.
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Affiliation(s)
- Tibor Tot
- Pathology & Cytology Dalarna, County Hospital Falun and Center for Clinical Research Dalarna, Falun, Sweden.
| | - Maria Gere
- Pathology & Cytology Dalarna, County Hospital Falun, Falun, Sweden
| | - Syster Hofmeyer
- Pathology & Cytology Dalarna, County Hospital Falun, Falun, Sweden
| | - Annette Bauer
- Pathology & Cytology Dalarna, County Hospital Dalarna, Falun, Sweden
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15
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Aljohani AI, Toss MS, Kurozumi S, Joseph C, Aleskandarany MA, Miligy IM, Ansari RE, Mongan NP, Ellis IO, Green AR, Rakha EA. The prognostic significance of wild-type isocitrate dehydrogenase 2 (IDH2) in breast cancer. Breast Cancer Res Treat 2019; 179:79-90. [PMID: 31599393 PMCID: PMC6985218 DOI: 10.1007/s10549-019-05459-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 09/25/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Lymphovascular invasion (LVI) is a prerequisite step in breast cancer (BC) metastasis. We have previously identified wild-type isocitrate dehydrogenase 2 (IDH2) as a key putative driver of LVI. Thus, we explored the prognostic significance of IDH2 at transcriptome and protein expression levels in pre-invasive and invasive disease. METHODS Utlising tissue microarrays from a large well annotated BC cohort including ductal carcinoma in situ and invasive breast cancer (IBC), IDH2 was assessed at the transcriptomic and proteomic level. The associations between clinicopathological factors including LVI status, prognosis and the expression of IDH2 were evaluated. RESULTS In pure DCIS and IBC, high IDH2 protein expression was associated with features of aggressiveness including high nuclear grade, larger size, comedo necrosis and hormonal receptor negativity and LVI, higher grade, larger tumour size, high NPI, HER2 positivity, and hormonal receptor negativity, respectively. High expression of IDH2 either in mRNA or in protein levels was associated with poor patient's outcome in both DCIS and IBC. Multivariate analysis revealed that IDH2 protein expression was an independent risk factor for shorter BC specific-survival. CONCLUSION Further functional studies to decipher the role of IDH2 and its mechanism of action as a driver of BC progression and LVI are warranted.
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Affiliation(s)
- Abrar I Aljohani
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK
| | - Michael S Toss
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK
| | - Sasagu Kurozumi
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK
| | - Chitra Joseph
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK
| | - Mohammed A Aleskandarany
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK
| | - Islam M Miligy
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK.,Histopathology Department, Faculty of Medicine, Menoufia University, Shibin El Kom, Egypt
| | - Rokaya El Ansari
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK
| | - Nigel P Mongan
- Department of Pharmacology, Weill Cornell Medicine, New York, 10065, USA.,Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, LE12 5RD, UK
| | - Ian O Ellis
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK
| | - Andrew R Green
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK
| | - Emad A Rakha
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK. .,Histopathology Department, Faculty of Medicine, Menoufia University, Shibin El Kom, Egypt. .,Department of Histopathology, Nottingham University Hospital NHS Trust, City Hospital Campus, Hucknall Road, Nottingham, NG5 1PB, UK.
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16
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Badve SS, Gökmen-Polar Y. Ductal carcinoma in situ of breast: update 2019. Pathology 2019; 51:563-569. [PMID: 31472981 DOI: 10.1016/j.pathol.2019.07.005] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 07/24/2019] [Accepted: 07/24/2019] [Indexed: 01/12/2023]
Abstract
Ductal carcinoma in situ is a non-invasive form of breast cancer. Its incidence is increasing due to widespread use of mammographic screening. It presents several diagnostic and management challenges in part due to its relatively indolent behaviour. Most series analysing biomarkers in these lesions are small (<100 patients) and large clinical trials have not been frequent. Herein, we review the recent progress made in understanding the biology of this entity and the tools available for prognostication.
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Affiliation(s)
- Sunil S Badve
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States.
| | - Yesim Gökmen-Polar
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States
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17
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Van Bockstal MR, Agahozo MC, Koppert LB, van Deurzen CHM. A retrospective alternative for active surveillance trials for ductal carcinoma in situ of the breast. Int J Cancer 2019; 146:1189-1197. [PMID: 31018242 PMCID: PMC7004157 DOI: 10.1002/ijc.32362] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/25/2019] [Accepted: 04/17/2019] [Indexed: 12/12/2022]
Abstract
Ductal carcinoma in situ (DCIS) of the breast is a nonobligate precursor of invasive breast cancer, accounting for 20 % of screen-detected breast cancers. Little is known about the natural progression of DCIS because most patients undergo surgery upon diagnosis. Many DCIS patients are likely being overtreated, as it is believed that only around 50 % of DCIS will progress to invasive carcinoma. Robust prognostic markers for progression to invasive carcinoma are lacking. In the past, studies have investigated women who developed a recurrence after breast-conserving surgery (BCS) and compared them with those who did not. However, where there is no recurrence, the patient has probably been adequately treated. The present narrative review advocates a new research strategy, wherein only those patients with a recurrence are studied. Approximately half of the recurrences are invasive cancers, and half are DCIS. So-called "recurrences" are probably most often the result of residual disease. The new approach allows us to ask: why did some residual DCIS evolve to invasive cancers and others not? This novel strategy compares the group of patients that developed in situ recurrence with the group of patients that developed invasive recurrence after BCS. The differences between these groups could then be used to develop a robust risk stratification tool. This tool should estimate the risk of synchronous and metachronous invasive carcinoma when DCIS is diagnosed in a biopsy. Identification of DCIS patients at low risk for developing invasive carcinoma will individualize future therapy and prevent overtreatment.
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Affiliation(s)
- Mieke R Van Bockstal
- Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Marie C Agahozo
- Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Linetta B Koppert
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
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18
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Sanati S. Morphologic and Molecular Features of Breast Ductal Carcinoma in Situ. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:946-955. [DOI: 10.1016/j.ajpath.2018.07.031] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 07/05/2018] [Accepted: 07/13/2018] [Indexed: 12/12/2022]
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19
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Van Bockstal M, Lambein K, Smeets A, Slembrouck L, Neven P, Nevelsteen I, Weltens C, Van Limbergen E, Christiaens MR, Van Ongeval C, Wildiers H, Libbrecht L, Floris G. Stromal characteristics are adequate prognosticators for recurrence risk in ductal carcinoma in situ of the breast. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2018; 45:550-559. [PMID: 30454971 DOI: 10.1016/j.ejso.2018.11.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 11/02/2018] [Accepted: 11/06/2018] [Indexed: 10/27/2022]
Abstract
BACKGROUND Ductal carcinoma in situ (DCIS) of the breast constitutes a heterogeneous group of non-obligate precursors for invasive breast cancer. To date, adequate risk stratification is lacking, which is presumed to result in overtreatment. We previously identified myxoid stromal architecture as a potential prognosticator for loco-regional recurrence. In the present study, we investigated the prognostic potential of stromal characteristics. METHODS Hematoxylin and eosin stained slides from 211 DCIS patients were reviewed. The following histological features were dichotomously assessed: nuclear grade, DCIS architecture, presence of necrosis, intraductal calcifications, stromal inflammation and myxoid stromal architecture. Loco-regional recurrences constituted the primary endpoint. RESULTS Cox regression analysis showed that high nuclear grade, myxoid stromal architecture and moderate to extensive stromal inflammation were significantly associated with decreased recurrence-free survival, independent of radiotherapy. Based on these features, a combined risk score (CRS) was calculated, ranging from zero to three. A high CRS of three was associated with significantly shorter recurrence-free survival. Nineteen patients had a CRS of three, of which three relapsed (15.7%), whereas only one out of 113 patients with a CRS of zero relapsed (0.9%). CONCLUSIONS We were able to validate our previously reported findings regarding the prognostic potential of myxoid periductal stroma in an independent DCIS patient cohort. A CRS based on nuclear grade, myxoid stromal architecture and stromal inflammation might facilitate discrimination of low risk from high risk patients. Consequently, the CRS may tailor adjuvant therapy. Future research should investigate whether radiotherapy can be safely omitted in patients with a low CRS.
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Affiliation(s)
- Mieke Van Bockstal
- Department of Pathology, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, the Netherlands; Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
| | - Kathleen Lambein
- Department of Pathology, AZ St Lucas Hospital Ghent, Groenebriel 1, 9000 Ghent, Belgium; Department of Surgical Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Ann Smeets
- Department of Surgical Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Laurence Slembrouck
- Department of Oncology, KUL University of Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Patrick Neven
- Department of Oncology, KUL University of Leuven, Herestraat 49, 3000 Leuven, Belgium; Department of Gynecology and Obstetrics, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Ines Nevelsteen
- Department of Surgical Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Caroline Weltens
- Department of Radiotherapy Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Erik Van Limbergen
- Department of Radiotherapy Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Marie-Rose Christiaens
- Department of Surgical Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Chantal Van Ongeval
- Department of Radiology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Hans Wildiers
- Department of Medical Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Louis Libbrecht
- Department of Pathology, University Clinics St Luc, Hippokrateslaan 10, 1200 Sint-Lambrechts-Woluwe, Belgium
| | - Giuseppe Floris
- Department of Pathology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium; Department of Imaging and Pathology, Laboratory of Translational Cell & Tissue Research, KUL University of Leuven, Herestraat 49, 3000 Leuven, Belgium
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20
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Molavi G, Samadi N, Hosseingholi EZ. The roles of moonlight ribosomal proteins in the development of human cancers. J Cell Physiol 2018; 234:8327-8341. [PMID: 30417503 DOI: 10.1002/jcp.27722] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 09/23/2018] [Indexed: 12/13/2022]
Abstract
"Moonlighting protein" is a term used to define a single protein with multiple functions and different activities that are not derived from gene fusions, multiple RNA splicing, or the proteolytic activity of promiscuous enzymes. Different proteinous constituents of ribosomes have been shown to have important moonlighting extra-ribosomal functions. In this review, we introduce the impact of key moonlight ribosomal proteins and dependent signal transduction in the initiation and progression of various cancers. As a future perspective, the potential role of these moonlight ribosomal proteins in the diagnosis, prognosis, and development of novel strategies to improve the efficacy of therapies for human cancers has been suggested.
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Affiliation(s)
- Ghader Molavi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasser Samadi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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21
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Van Bockstal M, Baldewijns M, Colpaert C, Dano H, Floris G, Galant C, Lambein K, Peeters D, Van Renterghem S, Van Rompuy AS, Verbeke S, Verschuere S, Van Dorpe J. Dichotomous histopathological assessment of ductal carcinoma in situ of the breast results in substantial interobserver concordance. Histopathology 2018; 73:923-932. [PMID: 30168167 DOI: 10.1111/his.13741] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/20/2018] [Indexed: 12/28/2022]
Abstract
AIMS Robust prognostic markers for ductal carcinoma in situ (DCIS) of the breast require high reproducibility and thus low interobserver variability. The aim of this study was to compare interobserver variability among 13 pathologists, in order to enable the identification of robust histopathological characteristics. METHODS AND RESULTS One representative haematoxylin and eosin-stained slide was selected for 153 DCIS cases. All pathologists independently assessed nuclear grade, intraductal calcifications, necrosis, solid growth, stromal changes, stromal inflammation, and apocrine differentiation. All characteristics were assessed categorically. Krippendorff's alpha was calculated to assess overall interobserver concordance. Cohen's kappa was calculated for every observer duo to further explore interobserver variability. The highest concordance was observed for necrosis, calcifications, and stromal inflammation. Assessment of solid growth, nuclear grade and stromal changes resulted in lower concordance. Poor concordance was observed for apocrine differentiation. Kappa values for each observer duo identified the 'ideal' cut-off for dichotomisation of multicategory variables. For instance, concordance was higher for 'non-high versus high' nuclear grade than for 'low versus non-low' nuclear grade. 'Absent/mild' versus 'moderate/extensive' stromal inflammation resulted in substantially higher concordance than other dichotomous cut-offs. CONCLUSIONS Dichotomous assessment of the histopathological features of DCIS resulted in moderate to substantial agreement among pathologists. Future studies on prognostic markers in DCIS should take into account this degree of interobserver variability to define cut-offs for categorically assessed histopathological features, as reproducibility is paramount for robust prognostic markers in daily clinical practice. A new prognostic index for DCIS might be considered, based on two-tier grading of histopathological features. Future research should explore the prognostic potential of such two-tier assessment.
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Affiliation(s)
- Mieke Van Bockstal
- Department of Pathology, Erasmus Medical Centre, Rotterdam, The Netherlands.,Department of Pathology, Ghent University Hospital, Ghent, Belgium
| | | | | | - Hélène Dano
- Department of Pathology, University Clinics St Luc, Brussels, Belgium
| | - Giuseppe Floris
- Department of Pathology, University Hospitals Leuven, Leuven, Belgium.,Department of Imaging and Pathology, Laboratory of Translational Cell & Tissue Research, KU Leuven, Leuven, Belgium
| | - Christine Galant
- Department of Pathology, University Clinics St Luc, Brussels, Belgium
| | - Kathleen Lambein
- Department of Pathology, AZ St Lucas Hospital, Ghent, Belgium.,Department of Surgical Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Dieter Peeters
- Department of Pathology, Antwerp University Hospital, Antwerp, Belgium
| | | | | | - Sofie Verbeke
- Department of Pathology, Ghent University Hospital, Ghent, Belgium
| | | | - Jo Van Dorpe
- Department of Pathology, Ghent University Hospital, Ghent, Belgium
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22
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Schultz S, Bartsch H, Sotlar K, Petat-Dutter K, Bonin M, Kahlert S, Harbeck N, Vogel U, Seeger H, Fehm T, Neubauer HJ. Progression-specific genes identified in microdissected formalin-fixed and paraffin-embedded tissue containing matched ductal carcinoma in situ and invasive ductal breast cancers. BMC Med Genomics 2018; 11:80. [PMID: 30236106 PMCID: PMC6147035 DOI: 10.1186/s12920-018-0403-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 09/06/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The transition from ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) is an important step during breast carcinogenesis. Understanding its molecular changes may help to identify high-risk DCIS that progress to IBC. Here, we describe a transcriptomic profiling analysis of matched formalin-fixed and paraffin-embedded (FFPE) DCIS and IBC components of individual breast tumours, containing both tumour compartments. The study was performed to validate progression-associated transcripts detected in an earlier gene profiling project using fresh frozen breast cancer tissue. In addition, FFPE tissues from patients with pure DCIS (pDCIS) were analysed to identify candidate transcripts characterizing DCIS with a high or low risk of progressing to IBC. METHODS Fifteen laser microdissected pairs of DCIS and IBC were profiled by Illumina DASL technology and used for expression validation by qPCR. Differential expression was independently validated using further 25 laser microdissected DCIS/IBC sample pairs. Additionally, laser microdissected epithelial cells from 31 pDCIS were investigated for expression of candidate transcripts using qPCR. RESULTS Multiple statistical calculation methods revealed 1784 mRNAs which are differentially expressed between DCIS and IBC (P < 0.05), of which 124 have also been identified in the gene profiling project using fresh frozen breast cancer tissue. Nine mRNAs that had been selected from the gene list obtained using fresh frozen tissues by applying pathway and network analysis (MMP11, GREM1, PLEKHC1, SULF1, THBS2, CSPG2, COL10A1, COL11A1, KRT14) were investigated in tissues from the same 15 microdissected specimens and the 25 independent tissue samples by qPCR. All selected transcripts were also detected in tumour cells from pDCIS. Expression of MMP11 and COL10A1 increased significantly from pDCIS to DCIS of DCIS/IBC mixed tumours. CONCLUSION We confirm differential expression of progression-associated transcripts in FFPE breast cancer samples which might mediate the transition from DCIS to IBC. MMP11 and COL10A1 may characterize pure DCIS with a high risk developing IDC.
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Affiliation(s)
- Silke Schultz
- Department of Obstetrics and Gynaecology, Life-Science-Center, Heinrich-Heine University, Merowingerplatz 1A, 40225, Duesseldorf, Germany
| | - Harald Bartsch
- Institute of Pathology, Department of Pathology, Ludwig Maximilians University, Thalkirchner Straße 36, 80337, Munich, Germany
| | - Karl Sotlar
- Institute of Pathology, Department of Pathology, Ludwig Maximilians University, Thalkirchner Straße 36, 80337, Munich, Germany
| | - Karina Petat-Dutter
- Institute of Pathology, Department of Pathology, Ludwig Maximilians University, Thalkirchner Straße 36, 80337, Munich, Germany
| | - Michael Bonin
- Microarray Facility, Department of Medical Genetics, Eberhard Karls University, Tuebingen, Germany.,IMGM Laboratories GmbH, Bunsenstr. 7a, 82152, Martinsried, Germany
| | - Steffen Kahlert
- Department of Obstetrics and Gynaecology, Ludwig Maximilians University, Marchioninistr. 15, 81377, Munich, Germany
| | - Nadia Harbeck
- Department of Obstetrics and Gynaecology, Ludwig Maximilians University, Marchioninistr. 15, 81377, Munich, Germany
| | - Ulrich Vogel
- Institute of Pathology, Eberhard Karls University, Tuebingen, Germany
| | - Harald Seeger
- Department of Obstetrics and Gynaecology, Eberhard Karls University, Liebermeisterstr. 8, 72076, Tuebingen, Germany.,Department of Obstetrics and Gynaecology, Eberhard Karls University, Calwerstr. 7, 72076, Tuebingen, Germany
| | - Tanja Fehm
- Department of Obstetrics and Gynaecology, Life-Science-Center, Heinrich-Heine University, Merowingerplatz 1A, 40225, Duesseldorf, Germany.,Department of Obstetrics and Gynaecology, Heinrich-Heine University, Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
| | - Hans J Neubauer
- Department of Obstetrics and Gynaecology, Life-Science-Center, Heinrich-Heine University, Merowingerplatz 1A, 40225, Duesseldorf, Germany.
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Ahmed W, Malik MFA, Saeed M, Haq F. Copy number profiling of Oncotype DX genes reveals association with survival of breast cancer patients. Mol Biol Rep 2018; 45:2185-2192. [PMID: 30225582 DOI: 10.1007/s11033-018-4379-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 09/10/2018] [Indexed: 12/17/2022]
Abstract
Copy number variations (CNVs) are key contributors in breast cancer initiation and progression. However, to date, no CNV-based gene signature is developed for breast cancer. 21-gene Oncotype DX, a clinically validated signature, was identified using only RNA expression data in breast cancer patients. In this study, we evaluated whether CNVs of Oncotype DX genes can be used to predict the prognosis of breast cancer patients. Transcriptomic data of 547 and genomic data of 816 of breast cancer patients were downloaded from The Cancer Genome Atlas database. To establish the prognostic relevance between the CNVs of Oncotype DX genes and clinicopathological features, statistical analysis including Pearson Correlation, Fisher-exact, Chi square, Kaplan-Meier survival and Cox regression analyses were performed. 86% genes showed positive CNV-expression correlation. CNVs in 52% and 47.6% genes showed association with ER+ and PR+ status, respectively. 71% of the genes (including ERBB2, CTSV, CD68, GRB7, MKI67, MMP1, PGR, RPLP0, TFRC, BAG1, BCL2, BIRC5, FLNB, GSTM1 and SCUBE2) showed association with poor overall survival. 14% of the genes (including CTSV, RPLP0 and BIRC5) genes showed association with disease free survival. Cox regression analysis revealed ESR1, metastasis and node stage as independent prognostic factors for overall survival of breast cancer patients. The results suggested that CNV-based assay of Oncotype DX genes can be used to predict the survival of breast cancer patients. In future, identifying new gene signatures for better breast cancer prognosis using CNV level information will be worth investigating.
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Affiliation(s)
- Washaakh Ahmed
- National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.,Department of Biosciences, COMSATS University, Islamabad, Pakistan
| | | | - Muhammad Saeed
- Department of Biosciences, COMSATS University, Islamabad, Pakistan
| | - Farhan Haq
- Department of Biosciences, COMSATS University, Islamabad, Pakistan.
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Knockdown of ribosomal protein S15A inhibits proliferation of breast cancer cells through induction of apoptosis in vitro. Cytotechnology 2018; 70:1315-1323. [PMID: 29802490 DOI: 10.1007/s10616-018-0221-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Accepted: 04/17/2018] [Indexed: 01/05/2023] Open
Abstract
To explore the role of ribosomal protein S15A (RPS15A) in breast cancer. The Oncomine database was used to compare the expression of RPS15A in human breast cancer tissues and normal tissues. RPS15A in breast cancer cell line ZR-75-30 and BT474 was specifically knocked down using lentivirus-mediated short hairpin RNAs (shRNAs). RPS15A knockdown efficiency was validated by quantitative polymerase chain reaction and western blot analysis. Subsequently, the functional effects of RPS15A on proliferation of breast cancer cells were investigated by MTT, colony formation and flow cytometry assays. Functional analysis indicated that RPS15A knockdown could inhibit cell proliferation, induced cell cycle arrest and apoptosis. Mechanism analysis revealed RPS15A mediated apoptosis via activating of caspase-3 and PARP cleavage, upregulating of Bad and BAX and downregulating of Bcl-2. Our preliminary study highlighted the importance of RPS15A in breast cancer growth. The inhibition of RPS15A may be a promising therapeutic target for breast cancer treatment.
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Abstract
Generation of intratumoral phenotypic and genetic heterogeneity has been attributed to clonal evolution and cancer stem cells that together give rise to a tumor with complex ecosystems. Each ecosystem contains various tumor cell subpopulations and stromal entities, which, depending upon their composition, can influence survival, therapy responses, and global growth of the tumor. Despite recent advances in breast cancer management, the disease has not been completely eradicated as tumors recur despite initial response to treatment. In this review, using data from clinically relevant breast cancer models, we show that the fates of tumor stem cells/progenitor cells in the individual tumor ecosystems comprising a tumor are predetermined to follow a limited (unipotent) and/or unlimited (multipotent) path of differentiation which create conditions for active generation and maintenance of heterogeneity. The resultant dynamic systems respond differently to treatments, thus disrupting the delicate stability maintained in the heterogeneous tumor. This raises the question whether it is better then to preserve stability by preventing takeover by otherwise dormant ecosystems in the tumor following therapy. The ultimate strategy for personalized therapy would require serial assessments of the patient's tumor for biomarker validation during the entire course of treatment that is combined with their three-dimensional mapping to the tumor architecture and landscape.
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26
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Breast carcinoma in sclerosing adenosis: a clinicopathological and immunophenotypical analysis on 206 lesions. J Clin Pathol 2018; 71:546-553. [DOI: 10.1136/jclinpath-2017-204751] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 11/26/2017] [Accepted: 12/04/2017] [Indexed: 11/03/2022]
Abstract
AimsTo fully elucidate the clinicopathological features of breast carcinoma in sclerosing adenosis (SA-BC).MethodsClinical and histological characteristics of 206 SA-BCs from 180 patients were retrospectively evaluated. Immunohistochemical phenotype was examined. The clinicopathological relevance of the topographical pattern of SA-BCs was analysed.ResultsOverall, up to 46 patients (25.6%) had contralateral cancer, either SA associated or not. Of 99 cases who underwent core needle biopsy (CNB), 36 were underestimated as adenosis or atypical ductal hyperplasia at CNB, 5 invasive cases were misinterpreted as in situ carcinomas, whereas 4 ductal carcinoma in situ (DCIS) cases were overdiagnosed as invasive carcinoma. Microscopically, 163 tumours were in situ, including 136 DCIS, 19 lobular carcinomas in situ (LCIS) and 8 mixed DCIS/LCIS; of these carcinomas in situ (CIS), 37 had microinvasion. The DCIS group exhibited low, intermediate and high grades in 53.7%, 34.6% and 11.8% of cases, respectively, mostly with solid (43.4%) or cribriform (41.9%) pattern. Forty out of 43 invasive cases were invasive ductal carcinoma (IDC), mostly DCIS predominant. Immunophenotypically, luminal A phenotype was identified in 55.1%, 63.2% and 45.0% of DCIS, LCIS and IDC cases, respectively. Topographical type A group (carcinoma being entirely confined to SA, n=176) was characterised by smaller size, less invasiveness, lower grade and more frequency of luminal A immunophenotype compared with type B group (≥ 50% but not all of the carcinomatous lesion being located in SA, n=30) (all P<0.05).ConclusionsCIS, especially non-high-grade DCIS, represents the most common variant of SA-BC, and luminal A is the most predominant immunophenotype. CNB assessment might be challenging in some SA-BCs. The topographical pattern has great clinicopathological relevance. Careful evaluation of the contralateral breast and long-term follow-up for patients with SA-BC is necessary given its high prevalence of bilaterality.
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Gorringe KL, Fox SB. Ductal Carcinoma In Situ Biology, Biomarkers, and Diagnosis. Front Oncol 2017; 7:248. [PMID: 29109942 PMCID: PMC5660056 DOI: 10.3389/fonc.2017.00248] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 10/02/2017] [Indexed: 12/21/2022] Open
Abstract
Ductal carcinoma in situ (DCIS) is an often-diagnosed breast disease and a known, non-obligate, precursor to invasive breast carcinoma. In this review, we explore the clinical and pathological features of DCIS, fundamental elements of DCIS biology including gene expression and genetic events, the relationship of DCIS with recurrence and invasive breast cancer, and the interaction of DCIS with the microenvironment. We also survey how these various elements are being used to solve the clinical conundrum of how to optimally treat a disease that has potential to progress, and yet is also likely over-treated in a significant proportion of cases.
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Affiliation(s)
- Kylie L. Gorringe
- Cancer Genomics Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
| | - Stephen B. Fox
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
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Current Approaches to Diagnosis and Treatment of Ductal Carcinoma In Situ and Future Directions. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 151:33-80. [PMID: 29096897 DOI: 10.1016/bs.pmbts.2017.08.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The presentation and treatment of ductal carcinoma in situ (DCIS) has changed substantially over the years. While previously an incidental pathologic finding in more advanced, palpable tumors, the institution of screening mammography has repositioned this disease entity as one largely diagnosed as a non-palpable lesion, often prior to any invasive disease. As DCIS is a precursor to invasive carcinoma, evolution in the approach to treatment has followed in the footsteps of that for invasive disease, including breast conservation therapy, adjuvant radiation, and use of antihormonal therapy. Survival outcomes for DCIS are very high and more recent literature has investigated tailoring therapeutic approaches to avoid overtreatment. Two important areas of ongoing clinical debate concerning overtreatment include use of preoperative MRI and the role of adjuvant radiation. The heterogeneity of the disease makes it difficult to differentiate lesions that would benefit from more aggressive treatment from those in which overtreatment could be avoided. Clinical characteristics, such as histologic appearance, age at diagnosis, and margin status at tumor excision have been established as moderate predictors of disease recurrence, but none has provided strong enough evidence as to guide consensus decisions on adjuvant therapy. Continuing research seeks to define the genetic and molecular characteristics that can predict disease course and serve as the potential targets for novel therapeutic agents. While several markers have shown promise in differentiating tumor aggressiveness, there is still much to be discovered about the precise mechanisms of disease progression and how this can be applied clinically to optimize treatment.
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29
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Progressive polarity loss and luminal collapse disrupt tissue organization in carcinoma. Genes Dev 2017; 31:1573-1587. [PMID: 28887414 PMCID: PMC5630022 DOI: 10.1101/gad.300566.117] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Accepted: 08/11/2017] [Indexed: 12/29/2022]
Abstract
Epithelial cancers (carcinoma) account for 80%-90% of all cancers. The development of carcinoma is associated with disrupted epithelial organization and solid ductal structures. The mechanisms underlying the morphological development of carcinoma are poorly understood, but it is thought that loss of cell polarity is an early event. Here we report the characterization of the development of human breast lesions leading to carcinoma. We identified a unique mechanism that generates solid ducts in carcinoma through progressive loss of polarity and collapse of the luminal architecture. This program initiates with asymmetric divisions of polarized cells that generate a stratified epithelium containing both polarized and depolarized cells. Stratified regions form cords that penetrate into the lumen, subdividing it into polarized secondary lumina. The secondary lumina then collapse with a concomitant decrease in RhoA and myosin II activity at the apical membrane and ultimately lose apical-basal polarity. By restoring RhoA activity in mice, ducts maintained lumen and cell polarity. Notably, disrupted tissue architecture through luminal collapse was reversible, and ducts with a lumen were re-established after oncogene suppression in vivo. This reveals a novel and common mechanism that contributes to carcinoma development by progressively disrupting cell and tissue organization.
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30
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Petrovic N, Davidovic R, Bajic V, Obradovic M, Isenovic RE. MicroRNA in breast cancer: The association with BRCA1/2. Cancer Biomark 2017; 19:119-128. [DOI: 10.3233/cbm-160319] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Onega T, Weaver DL, Frederick PD, Allison KH, Tosteson ANA, Carney PA, Geller BM, Longton GM, Nelson HD, Oster NV, Pepe MS, Elmore JG. The diagnostic challenge of low-grade ductal carcinoma in situ. Eur J Cancer 2017; 80:39-47. [PMID: 28535496 DOI: 10.1016/j.ejca.2017.04.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 03/30/2017] [Accepted: 04/05/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Diagnostic agreement among pathologists is 84% for ductal carcinoma in situ (DCIS). Studies of interpretive variation according to grade are limited. METHODS A national sample of 115 pathologists interpreted 240 breast pathology test set cases in the Breast Pathology Study and their interpretations were compared to expert consensus interpretations. We assessed agreement of pathologists' interpretations with a consensus reference diagnosis of DCIS dichotomised into low- and high-grade lesions. Generalised estimating equations were used in logistic regression models of rates of under- and over-interpretation of DCIS by grade. RESULTS We evaluated 2097 independent interpretations of DCIS (512 low-grade DCIS and 1585 high-grade DCIS). Agreement with reference diagnoses was 46% (95% confidence interval [CI] 42-51) for low-grade DCIS and 83% (95% CI 81-86) for high-grade DCIS. The proportion of reference low-grade DCIS interpretations over-interpreted by pathologists (i.e. categorised as either high-grade DCIS or invasive cancer) was 23% (95% CI 19-28); 30% (95% CI 26-34) were interpreted as a lower diagnostic category (atypia or benign proliferative). Reference high-grade DCIS was under-interpreted in 14% (95% CI 12-16) of observations and only over-interpreted 3% (95% CI 2-4). CONCLUSION Grade is a major factor when examining pathologists' variability in diagnosing DCIS, with much lower agreement for low-grade DCIS cases compared to high-grade. These findings support the hypothesis that low-grade DCIS poses a greater interpretive challenge than high-grade DCIS, which should be considered when developing DCIS management strategies.
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Affiliation(s)
- Tracy Onega
- Department of Biomedical Data Science, Department of Epidemiology, The Dartmouth Institute for Health Policy and Clinical Practice and Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
| | - Donald L Weaver
- Department of Pathology, University of Vermont and UVM Cancer Center, Burlington, VT, USA
| | - Paul D Frederick
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Kimberly H Allison
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Anna N A Tosteson
- Department of Medicine, The Dartmouth Institute for Health Policy and Clinical Practice and Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
| | - Patricia A Carney
- Department of Family Medicine, Oregon Health and Science University, Portland, OR, USA
| | - Berta M Geller
- Department of Family Medicine, University of Vermont, Burlington, VT 05401, USA
| | - Gary M Longton
- Department of Biostatistics, University of Washington, Seattle, WA 98101, USA
| | - Heidi D Nelson
- Providence Cancer Center, Providence Health and Services Oregon, and Department of Medical Informatics and Clinical Epidemiology and Department of Medicine, Oregon Health & Science University, Portland, OR, USA
| | - Natalia V Oster
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Margaret S Pepe
- Department of Biostatistics, University of Washington, Seattle, WA 98101, USA
| | - Joann G Elmore
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
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Sarper M, Allen MD, Gomm J, Haywood L, Decock J, Thirkettle S, Ustaoglu A, Sarker SJ, Marshall J, Edwards DR, Jones JL. Loss of MMP-8 in ductal carcinoma in situ (DCIS)-associated myoepithelial cells contributes to tumour promotion through altered adhesive and proteolytic function. Breast Cancer Res 2017; 19:33. [PMID: 28330493 PMCID: PMC5363009 DOI: 10.1186/s13058-017-0822-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 03/02/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Normal myoepithelial cells (MECs) play an important tumour-suppressor role in the breast but display an altered phenotype in ductal carcinoma in situ (DCIS), gaining tumour-promoter functions. Matrix metalloproteinase-8 (MMP-8) is expressed by normal MECs but is lost in DCIS. This study investigated the function of MMP-8 in MECs and the impact of its loss in DCIS. METHODS Primary normal and DCIS-associated MECs, and normal (N-1089) and DCIS-modified myoepithelial (β6-1089) cell lines, were used to assess MMP-8 expression and function. β6-1089 lacking MMP-8 were transfected with MMP-8 WT and catalytically inactive MMP-8 EA, and MMP-8 in N-1089 MEC was knocked down with siRNA. The effect on adhesion and migration to extracellular matrix (ECM), localisation of α6β4 integrin to hemidesmosomes (HD), TGF-β signalling and gelatinase activity was measured. The effect of altering MEC MMP-8 expression on tumour cell invasion was investigated in 2D and 3D organotypic models. RESULTS Assessment of primary cells and MEC lines confirmed expression of MMP-8 in normal MEC and its loss in DCIS-MEC. Over-expression of MMP-8 WT but not MMP-8 EA in β6-1089 cells increased adhesion to ECM proteins and reduced migration. Conversely, knock-down of MMP-8 in N-1089 reduced adhesion and increased migration. Expression of MMP-8 WT in β6-1089 led to greater localisation of α6β4 to HD and reduced retraction fibre formation, this being reversed by MMP-8 knock-down in N-1089. Over-expression of MMP-8 WT reduced TGF-β signalling and gelatinolytic activity. MMP-8 knock-down enhanced TGF-β signalling and gelatinolytic activity, which was reversed by blocking MMP-9 by knock-down or an inhibitor. MMP-8 WT but not MMP-8 EA over-expression in β6-1089 reduced breast cancer cell invasion in 2D and 3D invasion assays, while MMP-8 knock-down in N-1089 enhanced cancer cell invasion. Staining of breast cancer cases for MMP-8 revealed a statistically significant loss of MMP-8 expression in DCIS with invasion versus pure DCIS (p = 0.001). CONCLUSIONS These data indicate MMP-8 is a vital component of the myoepithelial tumour-suppressor function. It restores MEC interaction with the matrix, opposes TGF-β signalling and MMP-9 proteolysis, which contributes to inhibition of tumour cell invasion. Assessment of MMP-8 expression may help to determine risk of DCIS progression.
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Affiliation(s)
- Muge Sarper
- Translational Cancer Discovery Team, CRUK Cancer Therapeutics Unit, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK
| | - Michael D Allen
- Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
| | - Jenny Gomm
- Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Linda Haywood
- Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Julie Decock
- Cancer Research Centre, Qatar Biomedical Research Institute, Qatar Foundation, Doha, Qatar
| | - Sally Thirkettle
- Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Ahsen Ustaoglu
- Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Shah-Jalal Sarker
- Centre for Experimental Cancer Medicine, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - John Marshall
- Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Dylan R Edwards
- School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK
| | - J Louise Jones
- Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
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Diaz-Vera J, Palmer S, Hernandez-Fernaud JR, Dornier E, Mitchell LE, Macpherson I, Edwards J, Zanivan S, Norman JC. A proteomic approach to identify endosomal cargoes controlling cancer invasiveness. J Cell Sci 2017; 130:697-711. [PMID: 28062852 PMCID: PMC5339883 DOI: 10.1242/jcs.190835] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 12/15/2016] [Indexed: 12/17/2022] Open
Abstract
We have previously shown that Rab17, a small GTPase associated with epithelial polarity, is specifically suppressed by ERK2 (also known as MAPK1) signalling to promote an invasive phenotype. However, the mechanisms through which Rab17 loss permits invasiveness, and the endosomal cargoes that are responsible for mediating this, are unknown. Using quantitative mass spectrometry-based proteomics, we have found that knockdown of Rab17 leads to a highly selective reduction in the cellular levels of a v-SNARE (Vamp8). Moreover, proteomics and immunofluorescence indicate that Vamp8 is associated with Rab17 at late endosomes. Reduced levels of Vamp8 promote transition between ductal carcinoma in situ (DCIS) and a more invasive phenotype. We developed an unbiased proteomic approach to elucidate the complement of receptors that redistributes between endosomes and the plasma membrane, and have pin-pointed neuropilin-2 (NRP2) as a key pro-invasive cargo of Rab17- and Vamp8-regulated trafficking. Indeed, reduced Rab17 or Vamp8 levels lead to increased mobilisation of NRP2-containing late endosomes and upregulated cell surface expression of NRP2. Finally, we show that NRP2 is required for the basement membrane disruption that accompanies the transition between DCIS and a more invasive phenotype.
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Affiliation(s)
- Jesica Diaz-Vera
- Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK
| | - Sarah Palmer
- Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK
| | | | - Emmanuel Dornier
- Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK
| | - Louise E Mitchell
- Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK
| | - Iain Macpherson
- Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
| | - Joanne Edwards
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
| | - Sara Zanivan
- Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
| | - Jim C Norman
- Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
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Heng YJ, Lester SC, Tse GM, Factor RE, Allison KH, Collins LC, Chen YY, Jensen KC, Johnson NB, Jeong JC, Punjabi R, Shin SJ, Singh K, Krings G, Eberhard DA, Tan PH, Korski K, Waldman FM, Gutman DA, Sanders M, Reis-Filho JS, Flanagan SR, Gendoo DM, Chen GM, Haibe-Kains B, Ciriello G, Hoadley KA, Perou CM, Beck AH. The molecular basis of breast cancer pathological phenotypes. J Pathol 2016; 241:375-391. [PMID: 27861902 DOI: 10.1002/path.4847] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 10/21/2016] [Accepted: 11/01/2016] [Indexed: 12/21/2022]
Abstract
The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or reverse-phase protein assay subtype. Marked nuclear pleomorphism, necrosis, inflammation and a high mitotic count were associated with the basal-like subtype, and had a similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed by use of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of poorly differentiated epithelial tubules was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative breast cancer. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has the potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology, and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Yujing J Heng
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.,Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Susan C Lester
- Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
| | - Gary Mk Tse
- Department of Anatomical & Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong
| | - Rachel E Factor
- Department of Pathology, School of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Kimberly H Allison
- Department of Pathology, School of Medicine, Stanford Medical Center, Stanford University, Stanford, CA, USA
| | - Laura C Collins
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.,Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Yunn-Yi Chen
- Department of Pathology, School of Medicine, University of California, San Francisco, CA, USA
| | - Kristin C Jensen
- Department of Pathology, School of Medicine, Stanford Medical Center, Stanford University, Stanford, CA, USA.,VA Palo Alto Healthcare System, Palo Alto, CA, USA
| | - Nicole B Johnson
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.,Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Jong Cheol Jeong
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.,Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Rahi Punjabi
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.,Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Sandra J Shin
- Department of Pathology & Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Kamaljeet Singh
- Department of Pathology & Laboratory Medicine, Brown University, Providence, RI, USA
| | - Gregor Krings
- Department of Pathology, School of Medicine, University of California, San Francisco, CA, USA
| | - David A Eberhard
- Department of Pathology & Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Puay Hoon Tan
- Department of Pathology, Singapore General Hospital, Singapore
| | - Konstanty Korski
- Department of Pathology, Greater Poland Cancer Centre, Poznan, Poland
| | - Frederic M Waldman
- Department of Laboratory Medicine, School of Medicine, University of California, San Francisco, CA, USA
| | - David A Gutman
- Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, GA, USA
| | - Melinda Sanders
- Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, USA
| | - Jorge S Reis-Filho
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sydney R Flanagan
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.,Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Deena Ma Gendoo
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.,Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, ON, Canada
| | - Gregory M Chen
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Benjamin Haibe-Kains
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.,Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, ON, Canada
| | - Giovanni Ciriello
- Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
| | - Katherine A Hoadley
- Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Charles M Perou
- Department of Pathology & Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.,Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Andrew H Beck
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.,Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA
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Chang TT, Thakar D, Weaver VM. Force-dependent breaching of the basement membrane. Matrix Biol 2016; 57-58:178-189. [PMID: 28025167 DOI: 10.1016/j.matbio.2016.12.005] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 10/20/2016] [Accepted: 12/12/2016] [Indexed: 12/24/2022]
Abstract
Clinically, non-invasive carcinomas are confined to the epithelial side of the basement membrane and are classified as benign, whereas invasive cancers invade through the basement membrane and thereby acquire the potential to metastasize. Recent findings suggest that, in addition to protease-mediated degradation and chemotaxis-stimulated migration, basement membrane invasion by malignant cells is significantly influenced by the stiffness of the associated interstitial extracellular matrix and the contractility of the tumor cells that is dictated in part by their oncogenic genotype. In this review, we highlight recent findings that illustrate unifying molecular mechanisms whereby these physical cues contribute to tissue fibrosis and malignancy in three epithelial organs: breast, pancreas, and liver. We also discuss the clinical implications of these findings and the biological properties and clinical challenges linked to the unique biology of each of these organs.
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Affiliation(s)
- Tammy T Chang
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Liver Center, University of California, San Francisco, San Francisco, CA 94143, USA.
| | - Dhruv Thakar
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Bioengineering and Tissue Regeneration, University of California San Francisco, San Francisco, CA 94143, USA.
| | - Valerie M Weaver
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Bioengineering and Tissue Regeneration, University of California San Francisco, San Francisco, CA 94143, USA; Department of Anatomy, UCSF, San Francisco, CA 94143, USA; Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA 94143, USA; Department of Radiation Oncology, UCSF, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, CA 94143, USA; The Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA 94143, USA.
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37
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Petrovic N, Davidovic R, Jovanovic-Cupic S, Krajnovic M, Lukic S, Petrovic M, Roganovic J. Changes in miR-221/222 Levels in Invasive and In Situ Carcinomas of the Breast: Differences in Association with Estrogen Receptor and TIMP3 Expression Levels. Mol Diagn Ther 2016; 20:603-615. [PMID: 27488105 DOI: 10.1007/s40291-016-0230-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Breast cancer (BC) is a heterogeneous group of diseases that still represents a major cause of death in the female population. MicroRNAs (miRNAs, miRs), such as miR-221 and miR-222, have been shown to be involved in BC pathology by acting via its target genes such as tissue inhibitor of metalloproteinase 3 (TIMP3). OBJECTIVES The main goals of this study were to find differences in miR-221/222 levels of expression in BC groups based on invasiveness, and to investigate the association with estrogen receptor (ER), TIMP3 messenger RNA (mRNA) levels, and clinicopathological characteristics of patients and tumors. METHODS In this study, we measured levels of miR-221/222 in 63 breast tissue samples by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) using TaqMan® technology and immunohistochemistry. RESULTS miR-221/222 levels varied significantly across groups based on invasiveness (P < 0.001). In in situ tumors, miR-221 and miR-222 were negatively associated with ER (P = 0.001, r = -0.714, and P = 0.013, r = -0.585, respectively). In invasive breast carcinomas associated with non-invasive tumors, miR-222 was inversely associated with ER (P = 0.039, r = -0.620). Pure invasive BCs showed a positive correlation of miR-221 and miR-222 with TIMP3 mRNA levels (P = 0.008, r = 0.508, and P = 0.010, r = 0.497, respectively). CONCLUSION An increase in miR-221/222 might be an important event for in situ carcinoma formation, and miR-221/222 may be important molecules that highlight potential differences between invasive breast carcinomas associated with non-invasive and pure invasive BCs.
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Affiliation(s)
- Nina Petrovic
- Department for Radiobiology and Molecular Genetics, University of Belgrade-Vinca Institute of Nuclear Sciences, Mike Petrovica Alasa 12-14, 11001, Belgrade, Serbia.
| | - Radoslav Davidovic
- Department for Radiobiology and Molecular Genetics, University of Belgrade-Vinca Institute of Nuclear Sciences, Mike Petrovica Alasa 12-14, 11001, Belgrade, Serbia
| | - Snezana Jovanovic-Cupic
- Department for Radiobiology and Molecular Genetics, University of Belgrade-Vinca Institute of Nuclear Sciences, Mike Petrovica Alasa 12-14, 11001, Belgrade, Serbia
| | - Milena Krajnovic
- Department for Radiobiology and Molecular Genetics, University of Belgrade-Vinca Institute of Nuclear Sciences, Mike Petrovica Alasa 12-14, 11001, Belgrade, Serbia
| | - Silvana Lukic
- Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000, Belgrade, Serbia
| | - Milan Petrovic
- Clinic of Maxillofacial Surgery, School of Dental Medicine, University of Belgrade, Dr. Subotica 4, 11000, Belgrade, Serbia
| | - Jelena Roganovic
- Department of Pharmacology, School of Dental Medicine, University of Belgrade, Dr. Subotica 8, 11000, Belgrade, Serbia
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Elias EV, de Castro NP, Pineda PHB, Abuázar CS, de Toledo Osorio CAB, Pinilla MG, da Silva SD, Camargo AA, Silva WA, e Ferreira EN, Brentani HP, Carraro DM. Epithelial cells captured from ductal carcinoma in situ reveal a gene expression signature associated with progression to invasive breast cancer. Oncotarget 2016; 7:75672-75684. [PMID: 27708222 PMCID: PMC5342769 DOI: 10.18632/oncotarget.12352] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 09/20/2016] [Indexed: 12/21/2022] Open
Abstract
Breast cancer biomarkers that can precisely predict the risk of progression of non-invasive ductal carcinoma in situ (DCIS) lesions to invasive disease are lacking. The identification of molecular alterations that occur during the invasion process is crucial for the discovery of drivers of transition to invasive disease and, consequently, biomarkers with clinical utility. In this study, we explored differences in gene expression in mammary epithelial cells before and after the morphological manifestation of invasion, i.e., early and late stages, respectively. In the early stage, epithelial cells were captured from both pre-invasive lesions with distinct malignant potential [pure DCIS as well as the in situ component that co-exists with invasive breast carcinoma lesions (DCIS-IBC)]; in the late stage, epithelial cells were captured from the two distinct morphological components of the same sample (in situ and invasive components). Candidate genes were identified using cDNA microarray and rapid subtractive hybridization (RaSH) cDNA libraries and validated by RT-qPCR assay using new samples from each group. These analyses revealed 26 genes, including 20 from the early and 6 from the late stage. The expression profile based on the 20 genes, marked by a preferential decrease in expression level towards invasive phenotype, discriminated the majority of DCIS samples. Thus, this study revealed a gene expression signature with the potential to predict DCIS progression and, consequently, provides opportunities to tailor treatments for DCIS patients.
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Affiliation(s)
- Eliana Vanina Elias
- Laboratory of Genomics and Molecular Biology, CIPE-International Research Center, A.C. Camargo Cancer Center, São Paulo, SP, Brazil
| | - Nadia Pereira de Castro
- Laboratory of Genomics and Molecular Biology, CIPE-International Research Center, A.C. Camargo Cancer Center, São Paulo, SP, Brazil
| | - Paulo Henrique Baldan Pineda
- Laboratory of Genomics and Molecular Biology, CIPE-International Research Center, A.C. Camargo Cancer Center, São Paulo, SP, Brazil
| | - Carolina Sens Abuázar
- Laboratory of Genomics and Molecular Biology, CIPE-International Research Center, A.C. Camargo Cancer Center, São Paulo, SP, Brazil
| | | | - Mabel Gigliola Pinilla
- Laboratory of Genomics and Molecular Biology, CIPE-International Research Center, A.C. Camargo Cancer Center, São Paulo, SP, Brazil
| | - Sabrina Daniela da Silva
- Laboratory of Genomics and Molecular Biology, CIPE-International Research Center, A.C. Camargo Cancer Center, São Paulo, SP, Brazil
| | - Anamaria Aranha Camargo
- Ludwig Institute for Cancer Research, São Paulo, SP, Brazil
- Molecular Oncology Center, Sirio-Libanese Hospital, São Paulo, SP, Brazil
| | - Wilson Araujo Silva
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, SP, Brazil
| | - Elisa Napolitano e Ferreira
- Laboratory of Genomics and Molecular Biology, CIPE-International Research Center, A.C. Camargo Cancer Center, São Paulo, SP, Brazil
| | - Helena Paula Brentani
- Institute of Psychiatry-Medical School, University of São Paulo (FMUSP), São Paulo, SP, Brazil
| | - Dirce Maria Carraro
- Laboratory of Genomics and Molecular Biology, CIPE-International Research Center, A.C. Camargo Cancer Center, São Paulo, SP, Brazil
- National Institute of Science and Technology in Oncogenomics (INCITO), São Paulo, SP, Brazil
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Pang JMB, Gorringe KL, Fox SB. Ductal carcinoma in situ - update on risk assessment and management. Histopathology 2016; 68:96-109. [PMID: 26768032 DOI: 10.1111/his.12796] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 07/31/2015] [Indexed: 12/20/2022]
Abstract
Ductal carcinoma in situ (DCIS) accounts for ~20-25% of breast cancers. While DCIS is not life-threatening, it may progress to invasive carcinoma over time, and treatment intended to prevent invasive progression may itself cause significant morbidity. Accurate risk assessment is therefore necessary to avoid over- or undertreatment of an individual patient. In this review we will outline the evidence for current management of DCIS, discuss approaches to DCIS risk assessment and challenges facing identification of novel DCIS biomarkers.
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Affiliation(s)
- Jia-Min B Pang
- Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia.,Department of Pathology, University of Melbourne, Melbourne, Vic., Australia
| | - Kylie L Gorringe
- Department of Pathology, University of Melbourne, Melbourne, Vic., Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic., Australia.,Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia
| | - Stephen B Fox
- Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia.,Department of Pathology, University of Melbourne, Melbourne, Vic., Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic., Australia
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40
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Couderc C, Boin A, Fuhrmann L, Vincent-Salomon A, Mandati V, Kieffer Y, Mechta-Grigoriou F, Del Maestro L, Chavrier P, Vallerand D, Brito I, Dubois T, De Koning L, Bouvard D, Louvard D, Gautreau A, Lallemand D. AMOTL1 Promotes Breast Cancer Progression and Is Antagonized by Merlin. Neoplasia 2016; 18:10-24. [PMID: 26806348 PMCID: PMC4735628 DOI: 10.1016/j.neo.2015.11.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 11/18/2015] [Accepted: 11/23/2015] [Indexed: 11/29/2022] Open
Abstract
The Hippo signaling network is a key regulator of cell fate. In the recent years, it was shown that its implication in cancer goes well beyond the sole role of YAP transcriptional activity and its regulation by the canonical MST/LATS kinase cascade. Here we show that the motin family member AMOTL1 is an important effector of Hippo signaling in breast cancer. AMOTL1 connects Hippo signaling to tumor cell aggressiveness. We show that both canonical and noncanonical Hippo signaling modulates AMOTL1 levels. The tumor suppressor Merlin triggers AMOTL1 proteasomal degradation mediated by the NEDD family of ubiquitin ligases through direct interaction. In parallel, YAP stimulates AMOTL1 expression. The loss of Merlin expression and the induction of Yap activity that are frequently observed in breast cancers thus result in elevated AMOTL1 levels. AMOTL1 expression is sufficient to trigger tumor cell migration and stimulates proliferation by activating c-Src. In a large cohort of human breast tumors, we show that AMOTL1 protein levels are upregulated during cancer progression and that, importantly, the expression of AMOTL1 in lymph node metastasis appears predictive of the risk of relapse. Hence we uncover an important mechanism by which Hippo signaling promotes breast cancer progression by modulating the expression of AMOTL1.
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Affiliation(s)
| | - Alizée Boin
- Institut Curie, Paris, France; CNRS UMR144, Paris, France
| | - Laetitia Fuhrmann
- Institut Curie, Paris, France; CNRS UMR144, Paris, France; Department of Biopathology, Paris, France
| | - Anne Vincent-Salomon
- Institut Curie, Paris, France; Department of Biopathology, Paris, France; INSERM U934, Paris, France
| | - Vinay Mandati
- Institut Curie, Paris, France; CNRS UMR144, Paris, France
| | - Yann Kieffer
- Institut Curie, Paris, France; Stress and Cancer Laboratory, INSERM U830, France
| | | | | | | | - David Vallerand
- Institut Curie, Paris, France; Département de Recherche Translationnelle, Laboratoire d'Investigation Préclinique, Paris, France
| | - Isabelle Brito
- Institut Curie, Paris, France; INSERM U900, Paris, France; Mines ParisTech, Fontainebleau, France
| | - Thierry Dubois
- Institut Curie, Paris, France; Département de Recherche Translationnelle, Breast Cancer Biology Group, France
| | | | - Daniel Bouvard
- INSERM U823, Institut Albert Bonniot, Grenoble, France; Université Joseph Fourier, Grenoble, France
| | - Daniel Louvard
- Institut Curie, Paris, France; CNRS UMR144, Paris, France
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Lesurf R, Aure M, Mørk H, Vitelli V, Lundgren S, Børresen-Dale AL, Kristensen V, Wärnberg F, Hallett M, Sørlie T, Sauer T, Geisler J, Hofvind S, Borgen E, Børresen-Dale AL, Engebråten O, Fodstad Ø, Garred Ø, Geitvik G, Kåresen R, Naume B, Mælandsmo G, Russnes H, Schlichting E, Sørlie T, Lingjærde O, Kristensen V, Sahlberg K, Skjerven H, Fritzman B. Molecular Features of Subtype-Specific Progression from Ductal Carcinoma In Situ to Invasive Breast Cancer. Cell Rep 2016; 16:1166-1179. [DOI: 10.1016/j.celrep.2016.06.051] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 05/03/2016] [Accepted: 06/10/2016] [Indexed: 12/21/2022] Open
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Xu X, Xiong X, Sun Y. The role of ribosomal proteins in the regulation of cell proliferation, tumorigenesis, and genomic integrity. SCIENCE CHINA-LIFE SCIENCES 2016; 59:656-72. [DOI: 10.1007/s11427-016-0018-0] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 04/06/2016] [Indexed: 01/29/2023]
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Lo PK, Wolfson B, Zhou Q. Cancer stem cells and early stage basal-like breast cancer. World J Obstet Gynecol 2016; 5:150-161. [PMID: 28239564 PMCID: PMC5321620 DOI: 10.5317/wjog.v5.i2.150] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 10/21/2015] [Accepted: 01/22/2016] [Indexed: 02/05/2023] Open
Abstract
Ductal carcinoma in situ (DCIS) is a category of early stage, non-invasive breast tumor defined by the intraductal proliferation of malignant breast epithelial cells. DCIS is a heterogeneous disease composed of multiple molecular subtypes including luminal, HER2 and basal-like types, which are characterized by immunohistochemical analyses and gene expression profiling. Following surgical and radiation therapies, patients with luminal-type, estrogen receptor-positive DCIS breast tumors can benefit from adjuvant endocrine-based treatment. However, there are no available targeted therapies for patients with basal-like DCIS (BL-DCIS) tumors due to their frequent lack of endocrine receptors and HER2 amplification, rendering them potentially susceptible to recurrence. Moreover, multiple lines of evidence suggest that DCIS is a non-obligate precursor of invasive breast carcinoma. This raises the possibility that targeting precursor BL-DCIS is a promising strategy to prevent BL-DCIS patients from the development of invasive basal-like breast cancer. An accumulating body of evidence demonstrates the existence of cancer stem-like cells (CSCs) in BL-DCIS, which potentially determine the features of BL-DCIS and their ability to progress into invasive cancer. This review encompasses the current knowledge in regard to the characteristics of BL-DCIS, identification of CSCs, and their biological properties in BL-DCIS. We summarize recently discovered relevant molecular signaling alterations that promote the generation of CSCs in BL-DCIS and the progression of BL-DCIS to invasive breast cancer, as well as the influence of the tissue microenvironment on CSCs and the invasive transition. Finally, we discuss the translational implications of these findings for the prognosis and prevention of BL-DCIS relapse and progression.
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Chapa J, An G, Kulkarni SA. Examining the Relationship between Pre-Malignant Breast Lesions, Carcinogenesis and Tumor Evolution in the Mammary Epithelium Using an Agent-Based Model. PLoS One 2016; 11:e0152298. [PMID: 27023391 PMCID: PMC4811527 DOI: 10.1371/journal.pone.0152298] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 03/12/2016] [Indexed: 12/04/2022] Open
Abstract
INTRODUCTION Breast cancer, the product of numerous rare mutational events that occur over an extended time period, presents numerous challenges to investigators interested in studying the transformation from normal breast epithelium to malignancy using traditional laboratory methods, particularly with respect to characterizing transitional and pre-malignant states. Dynamic computational modeling can provide insight into these pathophysiological dynamics, and as such we use a previously validated agent-based computational model of the mammary epithelium (the DEABM) to investigate the probabilistic mechanisms by which normal populations of ductal cells could transform into states replicating features of both pre-malignant breast lesions and a diverse set of breast cancer subtypes. METHODS The DEABM consists of simulated cellular populations governed by algorithms based on accepted and previously published cellular mechanisms. Cells respond to hormones, undergo mitosis, apoptosis and cellular differentiation. Heritable mutations to 12 genes prominently implicated in breast cancer are acquired via a probabilistic mechanism. 3000 simulations of the 40-year period of menstrual cycling were run in wild-type (WT) and BRCA1-mutated groups. Simulations were analyzed by development of hyperplastic states, incidence of malignancy, hormone receptor and HER-2 status, frequency of mutation to particular genes, and whether mutations were early events in carcinogenesis. RESULTS Cancer incidence in WT (2.6%) and BRCA1-mutated (45.9%) populations closely matched published epidemiologic rates. Hormone receptor expression profiles in both WT and BRCA groups also closely matched epidemiologic data. Hyperplastic populations carried more mutations than normal populations and mutations were similar to early mutations found in ER+ tumors (telomerase, E-cadherin, TGFB, RUNX3, p < .01). ER- tumors carried significantly more mutations and carried more early mutations in BRCA1, c-MYC and genes associated with epithelial-mesenchymal transition. CONCLUSIONS The DEABM generates diverse tumors that express tumor markers consistent with epidemiologic data. The DEABM also generates non-invasive, hyperplastic populations, analogous to atypia or ductal carcinoma in situ (DCIS), via mutations to genes known to be present in hyperplastic lesions and as early mutations in breast cancers. The results demonstrate that agent-based models are well-suited to studying tumor evolution through stages of carcinogenesis and have the potential to be used to develop prevention and treatment strategies.
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Affiliation(s)
- Joaquin Chapa
- Pritzker School of Medicine, University of Chicago, 924 East 57th Street #104, Chicago, Illinois, 60637, United States of America
| | - Gary An
- Department of Surgery, University of Chicago, 5841 S. Maryland Ave, Chicago, Illinois, 60637, United States of America
| | - Swati A. Kulkarni
- Department of Surgery, Northwestern University, Robert H. Lurie Comprehensive Cancer Center, 303 E Superior Street, Lurie, 4–105, Chicago, Illinois, 60611, United States of America
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Mardekian SK, Bombonati A, Palazzo JP. Ductal carcinoma in situ of the breast: the importance of morphologic and molecular interactions. Hum Pathol 2015; 49:114-23. [PMID: 26826418 DOI: 10.1016/j.humpath.2015.11.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 11/02/2015] [Accepted: 11/05/2015] [Indexed: 12/21/2022]
Abstract
Ductal carcinoma in situ (DCIS) of the breast is a lesion characterized by significant heterogeneity, in terms of morphology, immunohistochemical staining, molecular signatures, and clinical expression. For some patients, surgical excision provides adequate treatment, but a subset of patients will experience recurrence of DCIS or progression to invasive ductal carcinoma (IDC). Recent years have seen extensive research aimed at identifying the molecular events that characterize the transition from normal epithelium to DCIS and IDC. Tumor epithelial cells, myoepithelial cells, and stromal cells undergo alterations in gene expression, which are most important in the early stages of breast carcinogenesis. Epigenetic modifications, such as DNA methylation, together with microRNA alterations, play a major role in these genetic events. In addition, tumor proliferation and invasion is facilitated by the lesional microenvironment, which includes stromal fibroblasts and macrophages that secrete growth factors and angiogenesis-promoting substances. Characterization of DCIS on a molecular level may better account for the heterogeneity of these lesions and how this manifests as differences in patient outcome and response to therapy. Molecular assays originally developed for assessing likelihood of recurrence in IDC are recently being applied to DCIS, with promising results. In the future, the classification of DCIS will likely incorporate molecular findings along with histologic and immunohistochemical features, allowing for personalized prognostic information and therapeutic options for patients with DCIS. This review summarizes current data regarding the molecular characterization of DCIS and discusses the potential clinical relevance.
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MESH Headings
- Animals
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/genetics
- Biopsy
- Breast Neoplasms/chemistry
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Breast Neoplasms/therapy
- Carcinoma/chemistry
- Carcinoma/genetics
- Carcinoma/pathology
- Carcinoma, Intraductal, Noninfiltrating/chemistry
- Carcinoma, Intraductal, Noninfiltrating/genetics
- Carcinoma, Intraductal, Noninfiltrating/pathology
- Carcinoma, Intraductal, Noninfiltrating/therapy
- Disease Progression
- Epigenesis, Genetic
- Female
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Humans
- Immunohistochemistry
- Mastectomy
- Molecular Diagnostic Techniques
- Neoplasm Recurrence, Local
- Phenotype
- Predictive Value of Tests
- Reproducibility of Results
- Treatment Outcome
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Affiliation(s)
- Stacey K Mardekian
- Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107.
| | - Alessandro Bombonati
- Department of Pathology, Albert Einstein Medical Center, Philadelphia, PA 19141.
| | - Juan P Palazzo
- Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107.
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46
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Yao Y, Liu Y, Lv X, Dong B, Wang F, Li J, Zhang Q, Xu R, Xu Y. Down-regulation of ribosomal protein S15A inhibits proliferation of human glioblastoma cells in vivo and in vitro via AKT pathway. Tumour Biol 2015; 37:4979-90. [PMID: 26537582 DOI: 10.1007/s13277-015-4323-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 10/26/2015] [Indexed: 01/13/2023] Open
Abstract
Ribosomal protein s15a (RPS15A), a highly conserved cytoplasmic protein, promotes mRNA/ribosome interaction in translation. Recent evidence showed that RPS15A is essential for tumor growth. RPS15A expression level was measured in glioblastoma tissue samples and normal brain (NB) tissue samples. RPS15A RNAi stable cell line U87 and U251 was generated by the pLVTHM-GFP lentiviral RNAi expression system. The knockdown efficiency was confirmed by quantitative real-time PCR and western blot. Molecular mechanisms and the effect of RPS15A on cell growth and migration were investigated by using western blot, MTT assay, wound healing assay, transwell migration assay, and tumorigenesis in nude mice. Here, we report that RPS15A is overexpressed in human glioblastoma tumor tissues. RPS15A knockdown inhibits proliferation and migration of glioblastoma cells in vitro. Knocking down RPS15A leads to the level of p-Akt decrease and cell cycle arrested in G0/G1 phase in U87 and U251 cells. Furthermore, the growth of glioblastoma cell-transplanted tumors in nude mice is inhibited by transduction with Lv-shRPS15A. Our findings indicate that RPS15A promotes cell proliferation and migration in glioblastoma for the first time. RPS15A might play a distinct role in glioblastoma and serve as a potential target for therapy.
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Affiliation(s)
- Yiqun Yao
- Department of Neurosurgery, First Affiliated Hospital, Dalian Medical University, 222 Zhong Shan Road, Dalian, 116011, People's Republic of China
| | - Yongjian Liu
- Department of interventional therapy, First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China
| | - Xiupeng Lv
- Department of Neurosurgery, First Affiliated Hospital, Dalian Medical University, 222 Zhong Shan Road, Dalian, 116011, People's Republic of China
| | - Bin Dong
- Department of Neurosurgery, First Affiliated Hospital, Dalian Medical University, 222 Zhong Shan Road, Dalian, 116011, People's Republic of China
| | - Feng Wang
- Department of interventional therapy, First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China
| | - Jun Li
- Department of Neurosurgery, First Affiliated Hospital, Dalian Medical University, 222 Zhong Shan Road, Dalian, 116011, People's Republic of China
| | - Qiuping Zhang
- Department of Pathology, First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China
| | - Ruixue Xu
- Department of Neurosurgery, First Affiliated Hospital, Dalian Medical University, 222 Zhong Shan Road, Dalian, 116011, People's Republic of China
| | - Yinghui Xu
- Department of Neurosurgery, First Affiliated Hospital, Dalian Medical University, 222 Zhong Shan Road, Dalian, 116011, People's Republic of China.
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47
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Zhang C, Zhang T, Song E, Himaya SWA, Chen X, Zheng L. Ribosomal protein S15A augments human osteosarcoma cell proliferation in vitro. Cancer Biother Radiopharm 2015; 29:451-6. [PMID: 25409460 DOI: 10.1089/cbr.2014.1698] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
As a highly conserved housekeeping gene, the biological implications of ribosomal protein S15A (RPS15A) during various processes, including carcinogenesis, remain elusive. Herein, the authors reported that knockdown of RPS15A expression significantly inhibited human osteosarcoma U2OS cell proliferation and colony formation in vitro by using a lentivirus-mediated RNA interference (RNAi) system. Moreover, an excess accumulation of cells in the G0/G1 phase was observed in U2OS cells transduced with lentivirus targeting RPS15A, suggesting that the growth inhibition mediated by RPS15A knockdown in osteosarcoma cells was probably due to the induction of cell cycle arrest. Taken together, this study highlights the crucial role of RPS15A in promoting osteosarcoma cell proliferation, and provides a foundation for further study into the clinical potential of inhibition of RPS15A for the treatment of osteosarcoma.
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Affiliation(s)
- Chen Zhang
- 1 Shanghai Tenth People's Hospital, Tongji University School of Medicine , Shanghai, China
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48
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Abba MC, Gong T, Lu Y, Lee J, Zhong Y, Lacunza E, Butti M, Takata Y, Gaddis S, Shen J, Estecio MR, Sahin AA, Aldaz CM. A Molecular Portrait of High-Grade Ductal Carcinoma In Situ. Cancer Res 2015; 75:3980-90. [PMID: 26249178 DOI: 10.1158/0008-5472.can-15-0506] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 07/09/2015] [Indexed: 12/30/2022]
Abstract
Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2(+)) displayed signatures characteristic of activated Treg cells (CD4(+)/CD25(+)/FOXP3(+)) and CTLA4(+)/CD86(+) complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.
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Affiliation(s)
- Martin C Abba
- CINIBA, School of Medical Sciences, National University of La Plata, La Plata, Argentina
| | - Ting Gong
- The University of Texas MD Anderson Cancer Center, Smithville, Texas
| | - Yue Lu
- The University of Texas MD Anderson Cancer Center, Smithville, Texas
| | - Jaeho Lee
- The University of Texas MD Anderson Cancer Center, Smithville, Texas
| | - Yi Zhong
- The University of Texas MD Anderson Cancer Center, Smithville, Texas
| | - Ezequiel Lacunza
- CINIBA, School of Medical Sciences, National University of La Plata, La Plata, Argentina
| | - Matias Butti
- CINIBA, School of Medical Sciences, National University of La Plata, La Plata, Argentina
| | - Yoko Takata
- The University of Texas MD Anderson Cancer Center, Smithville, Texas
| | - Sally Gaddis
- The University of Texas MD Anderson Cancer Center, Smithville, Texas
| | - Jianjun Shen
- The University of Texas MD Anderson Cancer Center, Smithville, Texas
| | - Marcos R Estecio
- The University of Texas MD Anderson Cancer Center, Smithville, Texas. The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Aysegul A Sahin
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - C Marcelo Aldaz
- The University of Texas MD Anderson Cancer Center, Smithville, Texas.
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49
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Borgquist S, Zhou W, Jirström K, Amini RM, Sollie T, Sørlie T, Blomqvist C, Butt S, Wärnberg F. The prognostic role of HER2 expression in ductal breast carcinoma in situ (DCIS); a population-based cohort study. BMC Cancer 2015; 15:468. [PMID: 26062614 PMCID: PMC4464713 DOI: 10.1186/s12885-015-1479-3] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 06/02/2015] [Indexed: 12/04/2022] Open
Abstract
Background HER2 is a well-established prognostic and predictive factor in invasive breast cancer. The role of HER2 in ductal breast carcinoma in situ (DCIS) is debated and recent data have suggested that HER2 is mainly related to in situ recurrences. Our aim was to study HER2 as a prognostic factor in a large population based cohort of DCIS with long-term follow-up. Methods All 458 patients diagnosed with a primary DCIS 1986–2004 in two Swedish counties were included. Silver-enhanced in situ hybridisation (SISH) was used for detection of HER2 gene amplification and protein expression was assessed by immunohistochemistry (IHC) in tissue microarrays. HER2 positivity was defined as amplified HER2 gene and/or HER2 3+ by IHC. HER2 status in relation to new ipsilateral events (IBE) and Invasive Breast Cancer Recurrences, local or distant (IBCR) was assessed by Kaplan-Meier survival analyses and Cox proportional hazards regression models. Results Primary DCIS was screening-detected in 75.5 % of cases. Breast conserving surgery (BCS) was performed in 78.6 % of whom 44.0 % received postoperative radiotherapy. No patients received adjuvant endocrine- or chemotherapy. The majority of DCIS could be HER2 classified (N = 420 (91.7 %)); 132 HER2 positive (31 %) and 288 HER2 negative (69 %)). HER2 positivity was related to large tumor size (P = 0.002), high grade (P < 0.001) and ER- and PR negativity (P < 0.001 for both). During follow-up (mean 184 months), 106 IBCRs and 105 IBEs were identified among all 458 cases corresponding to 54 in situ and 51 invasive recurrences. Eighteen women died from breast cancer and another 114 had died from other causes. The risk of IBCR was statistically significantly lower subsequent to a HER2 positive DCIS compared to a HER2 negative DCIS, (Log-Rank P = 0.03, (HR) 0.60 (95 % CI 0.38–0.94)). Remarkably, the curves did not separate until after 10 years. In ER-stratified analyses, HER2 positive DCIS was associated with lower risk of IBCR among women with ER negative DCIS (Log-Rank P = 0.003), but not for women with ER positive DCIS. Conclusions Improved prognostic tools for DCIS patients are warranted to tailor adjuvant therapy. Here, we demonstrate that HER2 positive disease in the primary DCIS is associated with lower risk of recurrent invasive breast cancer.
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Affiliation(s)
- Signe Borgquist
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Medicon Village Building 404:B3, Scheelevägen 2, SE-223 81, Lund, Sweden.
| | - Wenjing Zhou
- Department of Surgical Science, Uppsala University, Uppsala, SE-75105, Sweden.
| | - Karin Jirström
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Medicon Village Building 404:B3, Scheelevägen 2, SE-223 81, Lund, Sweden.
| | - Rose-Marie Amini
- Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
| | - Thomas Sollie
- Department of Pathology, Örebro University, Örebro, Sweden.
| | - Therese Sørlie
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Montebello, 0310, Oslo, Norway.
| | - Carl Blomqvist
- Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
| | - Salma Butt
- Department of Surgery, Clinical Sciences, Lund University, Malmö, Sweden.
| | - Fredrik Wärnberg
- Department of Surgical Science, Uppsala University, Uppsala, SE-75105, Sweden.
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50
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Lodillinsky C, Infante E, Guichard A, Chaligné R, Fuhrmann L, Cyrta J, Irondelle M, Lagoutte E, Vacher S, Bonsang-Kitzis H, Glukhova M, Reyal F, Bièche I, Vincent-Salomon A, Chavrier P. p63/MT1-MMP axis is required for in situ to invasive transition in basal-like breast cancer. Oncogene 2015; 35:344-57. [PMID: 25893299 DOI: 10.1038/onc.2015.87] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Revised: 01/29/2015] [Accepted: 02/22/2015] [Indexed: 01/01/2023]
Abstract
The transition of ductal carcinoma in situ (DCIS) to invasive breast carcinoma requires tumor cells to cross the basement membrane (BM). However, mechanisms underlying BM transmigration are poorly understood. Here, we report that expression of membrane-type 1 (MT1)-matrix metalloproteinase (MMP), a key component of the BM invasion program, increases during breast cancer progression at the in situ to invasive breast carcinoma transition. In the intraductal xenograft model, MT1-MMP is required for BM transmigration of MCF10DCIS.com breast adenocarcinoma cells and is overexpressed in cell clusters overlying focal BM disruptions and at the invasive tumor front. Mirrored upregulation of p63 and MT1-MMP is observed at the edge of MCF10DCIS.com xenograft tumors and p63 is required for induction of MT1-MMP-dependent invasive program in response to microenvironmental signals. Immunohistochemistry and analysis of public database reveal that p63 and MT1-MMP are upregulated in human basal-like breast tumors suggesting that p63/MT1-MMP axis contributes to progression of basal-like breast cancers with elevated p63 and MT1-MMP levels.
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Affiliation(s)
- C Lodillinsky
- Membrane and Cytoskeleton Dynamics Group, Cell Dynamics and Compartmentalization Unit, Institut Curie, Centre National de la Recherche Scientifique UMR144, Paris, France
| | - E Infante
- Membrane and Cytoskeleton Dynamics Group, Cell Dynamics and Compartmentalization Unit, Institut Curie, Centre National de la Recherche Scientifique UMR144, Paris, France
| | - A Guichard
- Membrane and Cytoskeleton Dynamics Group, Cell Dynamics and Compartmentalization Unit, Institut Curie, Centre National de la Recherche Scientifique UMR144, Paris, France
| | - R Chaligné
- Mammalian Developmental Epigenetics Group, Genetics and Developmental Biology Unit, Institut Curie, Paris, France
| | - L Fuhrmann
- Membrane and Cytoskeleton Dynamics Group, Cell Dynamics and Compartmentalization Unit, Institut Curie, Centre National de la Recherche Scientifique UMR144, Paris, France
| | - J Cyrta
- Membrane and Cytoskeleton Dynamics Group, Cell Dynamics and Compartmentalization Unit, Institut Curie, Centre National de la Recherche Scientifique UMR144, Paris, France
| | - M Irondelle
- Membrane and Cytoskeleton Dynamics Group, Cell Dynamics and Compartmentalization Unit, Institut Curie, Centre National de la Recherche Scientifique UMR144, Paris, France
| | - E Lagoutte
- Membrane and Cytoskeleton Dynamics Group, Cell Dynamics and Compartmentalization Unit, Institut Curie, Centre National de la Recherche Scientifique UMR144, Paris, France
| | - S Vacher
- Department of Genetics, Institut Curie, Paris, France
| | - H Bonsang-Kitzis
- RT2Lab Team, Translational Research Department, Institut Curie, Paris, France
| | - M Glukhova
- Molecular Mechanisms of Mammary Gland Development Group, Cell Dynamics and Compartmentalization Unit, Institut Curie, Centre National de la Recherche Scientifique UMR144, Paris, France
| | - F Reyal
- RT2Lab Team, Translational Research Department, Institut Curie, Paris, France
| | - I Bièche
- Department of Genetics, Institut Curie, Paris, France
| | - A Vincent-Salomon
- Mammalian Developmental Epigenetics Group, Genetics and Developmental Biology Unit, Institut Curie, Paris, France.,Pathology Department, Institut Curie, Paris, France
| | - P Chavrier
- Membrane and Cytoskeleton Dynamics Group, Cell Dynamics and Compartmentalization Unit, Institut Curie, Centre National de la Recherche Scientifique UMR144, Paris, France
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