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Patury CB, Santos BLM, Matos ALC, Slabi J, Gastalho LCC, Kaneto CM. Dysregulation of MiR-21, MiR-221 and MiR-451 During Neoadjuvant Treatment of Breast Cancer: A Prospective Study. Biomolecules 2024; 14:1580. [PMID: 39766287 PMCID: PMC11674781 DOI: 10.3390/biom14121580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/20/2024] [Accepted: 12/03/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Breast cancer is highly heterogeneous disease in which different responses are observed to the same treatment for different subtypes and extents of similar diseases. Considering this scenario, the search for tumor biomarkers is indispensable, with current evidence suggesting that circulating microRNAs are viable biomarkers. This study evaluated the expression of miR-21, miR-221, miR-195, and miR-451 in patients with breast cancer undergoing neoadjuvant treatment at oncology outpatient facilities in Brazil. METHODS We conducted a prospective and observational study in which blood samples were collected for microRNA expression analysis, comparing control and breast cancer patients who were candidates for neoadjuvant treatment groups. The expression of microRNAs was investigated by qRT-PCR method. For parametric data analysis, one-way ANOVA with Tukey's post hoc test was used. RESULTS Thirty-three participants (all female) were included in the control group and twenty-seven participants were included in the study group. The non-special subtype of breast cancer was found in 96% of the study group participants; 88.9% were locally advanced tumors (T3, T4), 40.7% were luminal tumors, 33.3% were HER-2-positive, and 26% were triple negative tumors. Expression analysis of microRNAs during neoadjuvant treatment, using miR-16 as a normalizer, showed higher expression levels of miR-21 and miR-221 at the end of treatment, and high expression levels for miR-451 were also observed at the beginning of treatment. CONCLUSION This is the first study that evaluates the expression of microRNAs in the context of neoadjuvant treatment of breast cancer in the Brazilian population. Our results suggest that there is a deregulation of miR-21, miR-221, and miR-451 during neoadjuvant treatment in these patients.
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Affiliation(s)
- Carine Bispo Patury
- Department of Health Science, Universidade Estadual de Santa Cruz, Ilhéus 45662-900, BA, Brazil; (C.B.P.); (J.S.)
| | - Brenda Luanny Maia Santos
- Department of Biological Science, Universidade Estadual de Santa Cruz, Ilhéus 45662-900, BA, Brazil; (B.L.M.S.); (A.L.C.M.); (L.C.C.G.)
| | - Anna Lucia Carvalho Matos
- Department of Biological Science, Universidade Estadual de Santa Cruz, Ilhéus 45662-900, BA, Brazil; (B.L.M.S.); (A.L.C.M.); (L.C.C.G.)
| | - José Slabi
- Department of Health Science, Universidade Estadual de Santa Cruz, Ilhéus 45662-900, BA, Brazil; (C.B.P.); (J.S.)
| | - Luciene Cristina Campos Gastalho
- Department of Biological Science, Universidade Estadual de Santa Cruz, Ilhéus 45662-900, BA, Brazil; (B.L.M.S.); (A.L.C.M.); (L.C.C.G.)
| | - Carla Martins Kaneto
- Department of Biological Science, Universidade Estadual de Santa Cruz, Ilhéus 45662-900, BA, Brazil; (B.L.M.S.); (A.L.C.M.); (L.C.C.G.)
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Tan S, Chen X, Liu W. Tumor-suppressive role of miR-139-5p in angiogenesis and tumorigenesis of ovarian cancer: Based on GEO microarray analysis and experimental validation. Cell Signal 2023; 109:110730. [PMID: 37244634 DOI: 10.1016/j.cellsig.2023.110730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/03/2023] [Accepted: 05/21/2023] [Indexed: 05/29/2023]
Abstract
This study clarified the possible molecular mechanisms by which the miR-139-5p/SOX4/TMEM2 axis affected angiogenesis and tumorigenesis of ovarian cancer (OC) based on GEO microarray datasets and experimental support. The expression of miR-139-5p and SOX4 was examined in clinical OC samples. Human umbilical vein endothelial cells (HUVECs) and human OC cell lines were included in vitro experiments. Tube formation assay was conducted in HUVECs. The expression of SOX4, SOX4, and VEGF in OC cells was identified using Western blot and immunohistochemistry. Luciferase assays were conducted to validate the targeting relationship between miR-139-5p and SOX4 and between SOX4 and TMEM2. A RIP assay assessed the binding of SOX4 and miR-139-5p. The impact of miR-139-5p and SOX4 on OC tumorigenesis in vivo was evaluated in nude mice. SOX4 was up-regulated, while miR-139-5p was down-regulated in OC tissues and cells. Ectopic miR-139-5p expression or SOX4 knockdown inhibited angiogenesis and tumorigenicity of OC. By targeting SOX4 in OC, miR-139-5p lowered VEGF expression, angiogenesis, and TMEM2 expression. The miR-139-5p/SOX4/TMEM2 axis also reduced VEGF expression and angiogenesis, which might curtail OC growth in vivo. Collectively, miR-139-5p represses VEGF expression and angiogenesis by targeting the transcription factor SOX4 and down-regulating TMEM2 expression, thereby impeding OC tumorigenesis.
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Affiliation(s)
- Shu Tan
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, PR China
| | - Xiuwei Chen
- Department of Gynecology Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, PR China
| | - Wei Liu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, PR China.
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Liu Y, Li J, Li J, Yan H, Qiao B, Wang Y, Hu Y, Sun C. The predictive value of MiR-221 in cancer chemoresistance: a systematic review and meta-analysis. Expert Rev Anticancer Ther 2023; 23:883-895. [PMID: 37272651 DOI: 10.1080/14737140.2023.2219451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 04/17/2023] [Indexed: 06/06/2023]
Abstract
BACKGROUND Many studies have reported that microRNA-221 (miR-221) is abnormally expressed in various cancers, and there has not been a study to systematically analyze the association between miR-221 and chemoresistance in different cancers. METHODS We systematically searched PubMed, Web of Science, Ovid, and Cochrane for relevant studies. The pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate. RESULTS A total of 30 studies with 1670 patients were enrolled in our study. Thirteen cancer types have been studied, and traditional chemotherapy, targeted drugs, endocrine therapy, chemoradiotherapy, and other treatments were used. High miR-221 expression was associated with poor chemotherapy response in most studies, and the meta-analysis confirmed this result (OR = 3.64, 95%CI: 1.73-7.62, p = 0.001). Besides, the higher level of miR-221 was related to shorter overall survival (OS) (HR = 2.16, 95%CI: 1.47-3.16, p < 0.001) and progression-free survival (PFS) (HR = 1.81, 95%CI: 1.51-2.16, p < 0.001) in patients after chemotherapy. CONCLUSION Our results highlight that high miR-221 expression has possible associations with chemoresistance and poor prognosis in multiple cancers. Further studies are needed to discover the molecular mechanisms underlying these associations to provide a solid evidence base for it being used as biomarkers of response to chemotherapeutic interventions in cancer.
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Affiliation(s)
- Yuxi Liu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingwen Li
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junying Li
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Han Yan
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bing Qiao
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yadan Wang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan, China
| | - Chunyan Sun
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan, China
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Singh S, Saini H, Sharma A, Gupta S, Huddar VG, Tripathi R. Breast cancer: miRNAs monitoring chemoresistance and systemic therapy. Front Oncol 2023; 13:1155254. [PMID: 37397377 PMCID: PMC10312137 DOI: 10.3389/fonc.2023.1155254] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 06/05/2023] [Indexed: 07/04/2023] Open
Abstract
With a high mortality rate that accounts for millions of cancer-related deaths each year, breast cancer is the second most common malignancy in women. Chemotherapy has significant potential in the prevention and spreading of breast cancer; however, drug resistance often hinders therapy in breast cancer patients. The identification and the use of novel molecular biomarkers, which can predict response to chemotherapy, might lead to tailoring breast cancer treatment. In this context, accumulating research has reported microRNAs (miRNAs) as potential biomarkers for early cancer detection, and are conducive to designing a more specific treatment plan by helping analyze drug resistance and sensitivity in breast cancer treatment. In this review, miRNAs are discussed in two alternative ways-as tumor suppressors to be used in miRNA replacement therapy to reduce oncogenesis and as oncomirs to lessen the translation of the target miRNA. Different miRNAs like miR-638, miR-17, miR-20b, miR-342, miR-484, miR-21, miR-24, miR-27, miR-23 and miR-200 are involved in the regulation of chemoresistance through diverse genetic targets. For instance, tumor-suppressing miRNAs like miR-342, miR-16, miR-214, and miR-128 and tumor-promoting miRNAs like miR101 and miR-106-25 cluster regulate the cell cycle, apoptosis, epithelial to mesenchymal transition and other pathways to impart breast cancer drug resistance. Hence, in this review, we have discussed the significance of miRNA biomarkers that could assist in providing novel therapeutic targets to overcome potential chemotherapy resistance to systemic therapy and further facilitate the design of tailored therapy for enhanced efficacy against breast cancer.
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Affiliation(s)
- Shivam Singh
- Department of Radiation Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Heena Saini
- Integrated translational Molecular Biology laboratory, Department of Rog Nidan and Vikriti vigyan (Pathology), All India Institute of Ayurveda (AIIA), New Delhi, India
| | - Ashok Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Subhash Gupta
- Department of Radiation Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - V. G. Huddar
- Department of Kaya Chikitsa (Internal Medicine), All India Institute of Ayurveda (AIIA), New Delhi, India
| | - Richa Tripathi
- Integrated translational Molecular Biology laboratory, Department of Rog Nidan and Vikriti vigyan (Pathology), All India Institute of Ayurveda (AIIA), New Delhi, India
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Szczepanek J, Skorupa M, Jarkiewicz-Tretyn J, Cybulski C, Tretyn A. Harnessing Epigenetics for Breast Cancer Therapy: The Role of DNA Methylation, Histone Modifications, and MicroRNA. Int J Mol Sci 2023; 24:ijms24087235. [PMID: 37108398 PMCID: PMC10138995 DOI: 10.3390/ijms24087235] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/24/2023] [Accepted: 04/10/2023] [Indexed: 04/29/2023] Open
Abstract
Breast cancer exhibits various epigenetic abnormalities that regulate gene expression and contribute to tumor characteristics. Epigenetic alterations play a significant role in cancer development and progression, and epigenetic-targeting drugs such as DNA methyltransferase inhibitors, histone-modifying enzymes, and mRNA regulators (such as miRNA mimics and antagomiRs) can reverse these alterations. Therefore, these epigenetic-targeting drugs are promising candidates for cancer treatment. However, there is currently no effective epi-drug monotherapy for breast cancer. Combining epigenetic drugs with conventional therapies has yielded positive outcomes and may be a promising strategy for breast cancer therapy. DNA methyltransferase inhibitors, such as azacitidine, and histone deacetylase inhibitors, such as vorinostat, have been used in combination with chemotherapy to treat breast cancer. miRNA regulators, such as miRNA mimics and antagomiRs, can alter the expression of specific genes involved in cancer development. miRNA mimics, such as miR-34, have been used to inhibit tumor growth, while antagomiRs, such as anti-miR-10b, have been used to inhibit metastasis. The development of epi-drugs that target specific epigenetic changes may lead to more effective monotherapy options in the future.
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Affiliation(s)
- Joanna Szczepanek
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, 87-100 Torun, Poland
| | - Monika Skorupa
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, 87-100 Torun, Poland
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 87-100 Torun, Poland
| | | | - Cezary Cybulski
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-204 Szczecin, Poland
| | - Andrzej Tretyn
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, 87-100 Torun, Poland
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 87-100 Torun, Poland
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6
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Is the microRNA-221/222 Cluster Ushering in a New Age of Cardiovascular Diseases? COR ET VASA 2023. [DOI: 10.33678/cor.2022.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
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Potential Role of Circulating miRNAs for Breast Cancer Management in the Neoadjuvant Setting: A Road to Pave. Cancers (Basel) 2023; 15:cancers15051410. [PMID: 36900200 PMCID: PMC10000233 DOI: 10.3390/cancers15051410] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/20/2023] [Accepted: 02/21/2023] [Indexed: 02/25/2023] Open
Abstract
Recently, circulating microRNAs (miRNAs) have emerged as potential non-invasive biomarkers for breast cancer (BC) management. In the context of BC patients undergoing neoadjuvant chemotherapy (NAC), the possibility of obtaining repeated, non-invasive biological samples from patients before, during, and after treatment is incredibly convenient and provides the opportunity to investigate circulating miRNAs as diagnostic, predictive, and prognostic tools. The present review aims to summarize major findings in this setting, thus highlighting their potential applicability in daily clinical practice and their possible limitations. In all the contexts (diagnostic, predictive, and prognostic), circulating miR-21-5p and miR-34a-5p have emerged as the most promising non-invasive biomarkers for BC patients undergoing NAC. Specifically, their high baseline level could discriminate between BC patients and healthy controls. On the other hand, in predictive and prognostic investigations, low circulating miR-21-5p and miR-34a-5p levels may identify patients with better outcomes, in terms of both treatment response and invasive disease-free survival. However, the findings in this field have been very heterogeneous. Indeed, pre-analytical and analytical variables, as well as factors related to patients, may explain the inconsistency among different study results. Thus, further clinical trials, with more precise patient inclusion criteria and more standardized methodological approaches, are definitely needed to better define the potential role of these promising non-invasive biomarkers.
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8
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miRNAs as therapeutic predictors and prognostic biomarkers of neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat 2022; 194:483-505. [PMID: 35727379 DOI: 10.1007/s10549-022-06642-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 05/30/2022] [Indexed: 11/02/2022]
Abstract
PURPOSE Accumulating evidence has shown that microRNAs (miRNAs) are promising biomarkers of neoadjuvant chemotherapy (NAC) response in breast cancer (BC). However, their predictive roles remain controversial. Thus, this systematic review and meta-analysis aimed to describe the role of miRNA expression in NAC response and prognosis in BC to increase statistical power and improve translation. METHODS A systematic review of electronic databases for relevant studies was conducted following PRISMA guidelines. Data were extracted, collated, and combined by odds ratio (OR) and hazard ratio (HR) with 95% confidence intervals (CIs) to estimate the strength of the associations. RESULTS Of the 560 articles screened, 59 studies were included in our systematic review, and 5 studies were included in the subsequent meta-analysis. Sixty of 123 miRNAs were found to be related with NAC response and an elevated baseline miR-7 level in tissues was associated with a higher pathological complete response rate (OR 5.63; 95% CI 2.15-14.79; P = 0.0004). The prognostic value of 39 miRNAs was also studied. Of them, 26 miRNAs were found to be associated with survival. Pooled HRs indicated that patients with increased levels of serum miR-21 from baseline to the end of the second NAC cycle and from baseline to the end of NAC had a worse disease-free survival than those with decreased levels. CONCLUSION Our results highlight that a large number of miRNAs have possible associations with NAC response and prognosis in BC patients. Further well-designed studies are needed to elucidate the molecular mechanisms underlying these associations.
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9
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Davey MG, Davey MS, Richard V, Wyns W, Soliman O, Miller N, Lowery AJ, Kerin MJ. Overview of MicroRNA Expression in Predicting Response to Neoadjuvant Therapies in Human Epidermal Growth Receptor-2 Enriched Breast Cancer - A Systematic Review. BREAST CANCER: BASIC AND CLINICAL RESEARCH 2022; 16:11782234221086684. [PMID: 35340888 PMCID: PMC8943461 DOI: 10.1177/11782234221086684] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 02/17/2022] [Indexed: 12/29/2022] Open
Abstract
Purpose: Increased appreciation of the human epidermal growth factor receptor-2
(HER2/neu) signalling pathway has led to the development of targeted
therapeutic agents used in conjunction with chemotherapy to improve outcomes
for HER2 overexpressing (HER2+) breast cancer. For neoadjuvant therapy,
response rates can be unpredictable – novel biomarkers predicting
effectiveness are required to enhance oncological outcomes for these
patients, and microRNA may prove effective. Our objective was to identify
microRNA (miRNA) expression patterns predictive of response to neoadjuvant
chemotherapy (NAC) and/or anti-HER2 targeted therapies in patients being
treated for early-stage HER2+ breast cancer. Methods: A search was performed of the PUBMED, SCOPUS, Web of Science, and EMBASE in
accordance to Preferred Reporting Items for Systematic Review and
Meta-Analyses (PRISMA) guidelines. Results: Overall, 15 studies including 1335 patients were included. These studies
highlighted an expression profile of 73 miRNA and their ability to predict
tumour response to neoadjuvant therapies was correlated. Results from 11
studies were in relation to circulatory miRNA and 4 studies included data
from tumour tissue. Overall, upregulation and downregulation of 41 miRNA and
29 miRNA, respectively, predicted differential response to neoadjuvant
therapy. Expression levels of 3 miRNA (miR-21, miR-210, and miR-376c-3p)
were inconclusive in predicting therapeutic response, while ‘aberrant’
expression of circulating miR-199a predicted pathological complete response
(pCR) to NAC. Conclusions: This systematic review outlines expression patterns of a number of miRNA
which correlate with response to NAC and/or anti-HER2 therapies. Future
translational research evaluating predictive biomarkers of primary response
to neoadjuvant therapy in HER2+ breast cancer may consider these
results.
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Affiliation(s)
- Matthew G Davey
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland, Galway, Galway, Ireland.,Precision Cardio-Oncology Research Enterprise (P-CORE), National University of Ireland, Galway, Galway, Ireland.,Department of Surgery, Galway University Hospitals, Galway, Ireland
| | - Martin S Davey
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland, Galway, Galway, Ireland
| | - Vinitha Richard
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland, Galway, Galway, Ireland.,Precision Cardio-Oncology Research Enterprise (P-CORE), National University of Ireland, Galway, Galway, Ireland
| | - William Wyns
- Precision Cardio-Oncology Research Enterprise (P-CORE), National University of Ireland, Galway, Galway, Ireland.,Discipline of Cardiology, CORRIB Core Laboratory, National University of Ireland, Galway, Galway, Ireland
| | - Osama Soliman
- Precision Cardio-Oncology Research Enterprise (P-CORE), National University of Ireland, Galway, Galway, Ireland.,Discipline of Cardiology, CORRIB Core Laboratory, National University of Ireland, Galway, Galway, Ireland
| | - Nicola Miller
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland, Galway, Galway, Ireland
| | - Aoife J Lowery
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland, Galway, Galway, Ireland.,Precision Cardio-Oncology Research Enterprise (P-CORE), National University of Ireland, Galway, Galway, Ireland
| | - Michael J Kerin
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland, Galway, Galway, Ireland.,Precision Cardio-Oncology Research Enterprise (P-CORE), National University of Ireland, Galway, Galway, Ireland
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Xia S, Lin Q. Estrogen Receptor Bio-Activities Determine Clinical Endocrine Treatment Options in Estrogen Receptor-Positive Breast Cancer. Technol Cancer Res Treat 2022; 21:15330338221090351. [PMID: 35450488 PMCID: PMC9036337 DOI: 10.1177/15330338221090351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
In estrogen receptor positive (ER+) breast cancer therapy, estrogen receptors (ERs) are the major targeting molecules. ER-targeted therapy has provided clinical benefits for approximately 70% of all breast cancer patients through targeting the ERα subtype. In recent years, mechanisms underlying breast cancer occurrence and progression have been extensively studied and largely clarified. The PI3K/AKT/mTOR pathway, microRNA regulation, and other ER downstream signaling pathways are found to be the effective therapeutic targets in ER+ BC therapy. A number of the ER+ (ER+) breast cancer biomarkers have been established for diagnosis and prognosis. The ESR1 gene mutations that lead to endocrine therapy resistance in ER+ breast cancer had been identified. Mutations in the ligand-binding domain of ERα which encoded by ESR1 gene occur in most cases. The targeted drugs combined with endocrine therapy have been developed to improve the therapeutic efficacy of ER+ breast cancer, particularly the endocrine therapy resistance ER+ breast cancer. The combination therapy has been demonstrated to be superior to monotherapy in overall clinical evaluation. In this review, we focus on recent progress in studies on ERs and related clinical applications for targeted therapy and provide a perspective view for therapy of ER+ breast cancer.
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Affiliation(s)
- Song Xia
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Qiong Lin
- School of Medicine, Jiangsu University, Zhenjiang, China
- Qiong Lin, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, China.
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11
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Tian JH, Liu SH, Yu CY, Wu LG, Wang LB. The Role of Non-Coding RNAs in Breast Cancer Drug Resistance. Front Oncol 2021; 11:702082. [PMID: 34589423 PMCID: PMC8473733 DOI: 10.3389/fonc.2021.702082] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 08/17/2021] [Indexed: 12/21/2022] Open
Abstract
Breast cancer (BC) is one of the commonly occurring malignancies in females worldwide. Despite significant advances in therapeutics, the mortality and morbidity of BC still lead to low survival and poor prognosis due to the drug resistance. There are certain chemotherapeutic, endocrine, and target medicines often used for BC patients, including anthracyclines, taxanes, docetaxel, cisplatin, and fluorouracil. The drug resistance mechanisms of these medicines are complicated and have not been fully elucidated. It was reported that non-coding RNAs (ncRNAs), such as micro RNAs (miRNA), long-chain non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) performed key roles in regulating tumor development and mediating therapy resistance. However, the mechanism of these ncRNAs in BC chemotherapeutic, endocrine, and targeted drug resistance was different. This review aims to reveal the mechanism and potential functions of ncRNAs in BC drug resistance and to highlight the ncRNAs as a novel target for achieving improved treatment outcomes for BC patients.
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Affiliation(s)
- Jin-Hai Tian
- The Biochip Research Center, General Hospital of Ningxia Medical University, Yinchuan, China, Yinchuan, China.,The Clinical Medicine College of Ningxia Medical University, Yinchuan, China
| | - Shi-Hai Liu
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chuan-Yang Yu
- The Biochip Research Center, General Hospital of Ningxia Medical University, Yinchuan, China, Yinchuan, China.,The Clinical Medicine College of Ningxia Medical University, Yinchuan, China
| | - Li-Gang Wu
- Department of Oncology, General Hospital of Ningxia Medical University, Yingchuan, China
| | - Li-Bin Wang
- The Biochip Research Center, General Hospital of Ningxia Medical University, Yinchuan, China, Yinchuan, China.,The Clinical Medicine College of Ningxia Medical University, Yinchuan, China
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12
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The Role of MicroRNA as Clinical Biomarkers for Breast Cancer Surgery and Treatment. Int J Mol Sci 2021; 22:ijms22158290. [PMID: 34361056 PMCID: PMC8346977 DOI: 10.3390/ijms22158290] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/29/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is the most common cancer diagnosed in women. In recent times, survival outcomes have improved dramatically in accordance with our enhanced understanding of the molecular processes driving breast cancer proliferation and development. Refined surgical approaches, combined with novel and targeted treatment options, have aided the personalisation of breast cancer patient care. Despite this, some patients will unfortunately succumb to the disease. In recent times, translational research efforts have been focused on identifying novel biomarkers capable of informing patient outcome; microRNAs (miRNAs) are small non-coding molecules, which regulate gene expression at a post-transcriptional level. Aberrant miRNA expression profiles have been observed in cancer proliferation and development. The measurement and correlation of miRNA expression levels with oncological outcomes such as response to current conventional therapies, and disease recurrence are being investigated. Herein, we outline the clinical utility of miRNA expression profiles in informing breast cancer prognosis, predicting response to treatment strategies as well as their potential as therapeutic targets to enhance treatment modalities in the era of precision oncology.
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13
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Pan X, Hong X, Li S, Meng P, Xiao F. METTL3 promotes adriamycin resistance in MCF-7 breast cancer cells by accelerating pri-microRNA-221-3p maturation in a m6A-dependent manner. Exp Mol Med 2021; 53:91-102. [PMID: 33420414 PMCID: PMC8080609 DOI: 10.1038/s12276-020-00510-w] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 07/14/2020] [Accepted: 08/10/2020] [Indexed: 01/29/2023] Open
Abstract
Breast cancer (BC) is the most prevalent malignant neoplasm among women and is the fifth most common cause of cancer-associated death worldwide. Acquired chemoresistance driven by genetic and epigenetic alterations is a significant clinical challenge in treating BC. However, the mechanism of BC cell resistance to adriamycin (ADR) remains to be elucidated. In this study, we identified the methyltransferase-like 3/microRNA-221-3p/homeodomain-interacting protein kinase 2/Che-1 (METTL3/miR-221-3p/HIPK2/Che-1) axis as a novel signaling event that may be responsible for resistance of BC cells to ADR. A dual-luciferase reporter gene assay was employed to test the presence of miR-221-3p binding sites in the 3'UTR of HIPK2. Drug resistance was evaluated by immunoblotting multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP). Cultured ADR-resistant MCF-7 cells were assayed for their half maximal inhibitory concentration (IC50) values and apoptosis using an MTT assay and Annexin V-FITC/PI-labeled flow cytometry, and the cells were then xenografted into nude mice. METTL3 knockdown was shown to reduce the expression of miR-221-3p by reducing pri-miR-221-3p m6A mRNA methylation, thereby reducing the IC50 value of ADR-resistant MCF-7 cells, reducing the expression of MDR1 and BCRP, and inducing apoptosis. Mechanistically, miR-221-3p was demonstrated to negatively regulate HIPK2 and upregulate its direct target Che-1, thus leading to enhanced drug resistance in ADR-resistant MCF-7 cells. In vitro results were reproduced in nude mice xenografted with ADR-resistant MCF-7 cells. Our work elucidates an epigenetic mechanism of acquired chemoresistance in BC, in support of the METTL3/miR-221-3p/HIPK2/Che-1 axis as a therapeutic target for the improvement of chemotherapy.
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Affiliation(s)
- Xiaoping Pan
- grid.284723.80000 0000 8877 7471Clinical Laboratory, Huadu Hospital, Southern Medical University, 510800 Guangzhou, P. R. China
| | - Xiaolv Hong
- grid.284723.80000 0000 8877 7471Department of Infectious Disease, Huadu Hospital, Southern Medical University, 510800 Guangzhou, P. R. China
| | - Sumei Li
- grid.284723.80000 0000 8877 7471Clinical Laboratory, Huadu Hospital, Southern Medical University, 510800 Guangzhou, P. R. China
| | - Ping Meng
- grid.284723.80000 0000 8877 7471Central Laboratory, Huadu Hospital, Southern Medical University, 510800 Guangzhou, P. R. China
| | - Feng Xiao
- grid.284723.80000 0000 8877 7471Clinical Laboratory, Huadu Hospital, Southern Medical University, 510800 Guangzhou, P. R. China
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14
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Liquid biopsy for breast cancer using extracellular vesicles and cell-free microRNAs as biomarkers. Transl Res 2020; 223:40-60. [PMID: 32413499 DOI: 10.1016/j.trsl.2020.04.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 03/31/2020] [Accepted: 04/07/2020] [Indexed: 12/24/2022]
Abstract
Improvement of breast cancer (BC) patient's outcome is directly related to early detection. However, there is still a lack of reliable biomarkers for diagnosis, prognosis and, treatment follow up in BC, leading researchers to study the potential of liquid biopsy based on circulating microRNAs (c-miRNAs). These c-miRNAs can be cell-free or associated with extracellular vesicles (EVs), and have great advantages such as stability in biofluids, noninvasive accessibility compared to current techniques (core-biopsy and surgery), and expression associated with pathogenic conditions. Recently, a new promising field of EV-derived miRNAs (EV-miRNAs) as cancer biomarkers has emerged, receiving special attention due to their selective vesicle sorting which makes them accurate for disease detection. In this review, we discuss new findings about c-miRNA and their potential as biomarkers for BC diagnosis, prognosis, and therapy. Additionally, we address the impact of limitations associated with the standardization of analysis techniques and methods on the implementation of these biomarkers in the clinical setting.
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15
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Xu W, Chen X, Deng F, Zhang J, Zhang W, Tang J. Predictors of Neoadjuvant Chemotherapy Response in Breast Cancer: A Review. Onco Targets Ther 2020; 13:5887-5899. [PMID: 32606799 PMCID: PMC7320215 DOI: 10.2147/ott.s253056] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 05/18/2020] [Indexed: 12/17/2022] Open
Abstract
Neoadjuvant chemotherapy (NAC) largely increases operative chances and improves prognosis of the local advanced breast cancer patients. However, no specific means have been invented to predict the therapy responses of patients receiving NAC. Therefore, we focus on the alterations of tumor tissue-related microenvironments such as stromal tumor-infiltrating lymphocytes status, cyclin-dependent kinase expression, non-coding RNA transcription or other small molecular changes, in order to detect potentially predicted biomarkers which reflect the therapeutic efficacy of NAC in different subtypes of breast cancer. Further, possible mechanisms are also discussed to discover feasible treatment targets. Thus, these findings will be helpful to promote the prognosis of breast cancer patients who received NAC and summarized in this review.
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Affiliation(s)
- Weilin Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Xiu Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Fei Deng
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Jian Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Wei Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China
| | - Jinhai Tang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China
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16
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Zhang Z, Li W, Jiang D, Liu C, Lai Z. MicroRNA-139-5p inhibits cell viability, migration and invasion and suppresses tumor growth by targeting HDGF in non-small cell lung cancer. Oncol Lett 2020; 19:1806-1814. [PMID: 32194674 PMCID: PMC7039177 DOI: 10.3892/ol.2020.11296] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 07/10/2019] [Indexed: 12/13/2022] Open
Abstract
MicroRNA (miRNAs) serve key roles in the progress of various types of cancer. The expression of miRNA (miR)-139-5p is downregulated in several types of tumor and has been recognized as a tumor suppressor. However, the role of miR-139-5p in non-small cell lung cancer (NSCLC) has not been investigated in detail. In the present study, it was demonstrated that miR-139-5p was significantly downregulated in NSCLC cells and tissues, and the overexpression of miR-139-5p in vitro induced apoptosis and significantly inhibited the viability and proliferation of A549 and H1299 cells. In addition, upregulation of miR-139-5p significantly inhibited the migration and invasion of A549 and H1299 cells. Hepatoma-derived growth factor (HDGF) was identified as a direct target of miR-139-5p. Rescue experiments demonstrated that the inhibitory function of miR-139-5p on cell viability, migration and invasion was partially mediated by suppressing HDGF expression. Furthermore, miR-139-5p exhibited efficient inhibition of tumor growth in a xenograft tumor mouse model of A549 cells. In summary, the results from the present study suggested that miR-139-5p may serve an important role in NSCLC by targeting HDGF and causing inhibition of cell viability and metastasis, as well as induction of apoptosis. miR-139-5p may also have the potential to serve as a therapeutic target for the treatment of NSCLC.
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Affiliation(s)
- Zuxiong Zhang
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Weizhi Li
- Department of Radiotherapy, Tumor Hospital of Ganzhou, Ganzhou, Jiangxi 341000, P.R. China
| | - Damei Jiang
- Department of Obstetrics and Gynecology, Ganzhou Municipal Hospital, Ganzhou, Jiangxi 341000, P.R. China
| | - Chi Liu
- School of Medical and Life Sciences, Chengdu University of TCM, Chengdu, Sichuan 610072, P.R. China
| | - Zhenghong Lai
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
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17
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Liu K, Wang L, Sun E. Prognostic value of miR-221 in human malignancy: evidence from 3041 subjects. BMC Cancer 2019; 19:867. [PMID: 31470827 PMCID: PMC6717359 DOI: 10.1186/s12885-019-6079-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Accepted: 08/23/2019] [Indexed: 01/05/2023] Open
Abstract
Background MiR-221, acting as onco-miR or oncosuppressor-miR, plays an important role in tumor progression; however, the prognostic value of miR-221 in human carcinomas is controversial and inconclusive. The objective of our study was to conducted a systematic review and meta-analysis of miR-221 in various types of human cancers. Methods An online search of up-to-date electronic databases, including PubMed and Embase, was conducted to identify as many relevant papers as possible. 32 papers involving 3041 patients with different carcinomas were included in the analysis. Hazard ratios (HRs) of miR-221 were used to evaluate prognostic values. Results Thirty-two papers involving 15 cancers were included. MiR-221 was associated with a worse overall survival (OS) in patients, and a combined HR was 1.93 (95% CI of 1.43–2.60, 2080 patients, 22 studies, I-squared = 80.4%, P = 0.000); however, the combined HR for relapse-free survival (RFS) was 1.37 (95% CI of 0.75–2.48, 625 patients, 7 studies, I-squared = 78.8%, P = 0.000), and disease-free survival (DFS) was 1.24 (95% CI of 0.60–2.56, 539 patients, 5 studies, I-squared = 81.8%, P = 0.000). Conclusion MiR-221 was shown to be associated with a poor OS in human carcinomas, and thus may serve as a useful predictor of clinical outcomes. Electronic supplementary material The online version of this article (10.1186/s12885-019-6079-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kangkang Liu
- Department of Urology, Tianjin institute of urology, The 2nd Hospital of Tianjin Medical University, No 23, PingJiang Road, Hexi District, Tianjin, 300211, People's Republic of China
| | - Lining Wang
- Department of Urology, Tianjin institute of urology, The 2nd Hospital of Tianjin Medical University, No 23, PingJiang Road, Hexi District, Tianjin, 300211, People's Republic of China
| | - Erlin Sun
- Department of Urology, Tianjin institute of urology, The 2nd Hospital of Tianjin Medical University, No 23, PingJiang Road, Hexi District, Tianjin, 300211, People's Republic of China.
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18
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Shao B, Wang X, Zhang L, Li D, Liu X, Song G, Cao H, Zhu J, Li H. Plasma microRNAs Predict Chemoresistance in Patients With Metastatic Breast Cancer. Technol Cancer Res Treat 2019; 18:1533033819828709. [PMID: 30786836 PMCID: PMC6383099 DOI: 10.1177/1533033819828709] [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] [Indexed: 11/16/2022] Open
Abstract
Background: MicroRNAs contribute to chemotherapy response in different types
of cancer. We hypothesized that plasma miRNAs are potentially associated with chemotherapy
response in patients with metastatic breast cancer. Patients and Methods: Fourteen
candidate microRNAs were chosen from the literature, and their plasma levels were measured
by quantitative polymerase chain reaction (PCR). Forty metastatic breast cancer patients
were chosen as the training groups. The potential significant microRNAs were validated in
another 103 plasma samples. Results: In the training set, we identified 3 microRNAs
(miR-200a, miR-210, and miR-451) as significantly dysregulated miRNAs between sensitive
group (partial response (and stable disease) and resistant group (progressive disease).
Then, in the validation set, miR-200a (area under the curve = 0.881, sensitivity = 94.1%,
specificity = 76.7%) and miR-210 (area under the curve = 0.851, sensitivity = 88.2%,
specificity = 72.1%) showed high diagnostic accuracy for distinguishing sensitive group
from resistant group. Furthermore, the plasma level of miR-200a was significantly
associated with the stage in surgery (P = .035), and the high level of
miR-210 expression was associated with internal organ metastasis (liver, lung, and brain;
P = .024). Conclusions: Plasma miR-200a and miR-210 could be effective
biomarkers for the prediction of chemotherapy resistance in metastatic breast cancer
patients.
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Affiliation(s)
- Bin Shao
- 1 Department of Medical Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Xiaoxia Wang
- 2 Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University, Beijing, People's Republic of China
| | - Lei Zhang
- 2 Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University, Beijing, People's Republic of China
| | - Deyu Li
- 3 Kunshan RNAi institute, Kunshan, Jiangsu province, People's Republic of China
| | - Xiaoran Liu
- 1 Department of Medical Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Guohong Song
- 1 Department of Medical Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Huiqing Cao
- 2 Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University, Beijing, People's Republic of China
| | - Jun Zhu
- 1 Department of Medical Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Huiping Li
- 1 Department of Medical Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
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19
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Wang XX, Ye FG, Zhang J, Li JJ, Chen QX, Lin PY, Song CG. Serum miR-4530 sensitizes breast cancer to neoadjuvant chemotherapy by suppressing RUNX2. Cancer Manag Res 2018; 10:4393-4400. [PMID: 30349372 PMCID: PMC6188109 DOI: 10.2147/cmar.s172205] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Purpose Neoadjuvant chemotherapy (NAC) plays a pivotal role in the treatment of locally advanced breast cancer (LABC); however, breast cancer is a heterogeneous disease, individual responses to chemotherapy are highly variable. Therefore, the purpose of the current research is to identify biomarkers that can predict the chemotherapeutic response. Patients and methods We recruited 78 patients with primary breast cancer who underwent taxane- and anthracycline-based NAC; these patients were divided into sensitive and resistant groups according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The microRNA microarray was conducted to explore differentially expressed miRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) further validated the relationship between miR-4530 and chemosensitivity in breast cancer patients. Results No significant differences were observed between the two groups regarding the clinicopathological characteristics. miR-4530 showed the most potential involving breast cancer chemosensitivity. Mechanically, RUNX2 was identified one of the direct targets of miR-4530 and responsible for breast cancer chemosensitivity. Conclusion Our results revealed that elevated serum miR-4530 levels may sensitize breast cancer to taxane- and anthracycline-based NAC by suppressing RUNX2; therefore, this miRNA has the potential to be a new biomarker for predicting breast cancer chemosensitivity.
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Affiliation(s)
- Xiao-Xiao Wang
- Department of Breast Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou, People's Republic of China,
| | - Fu-Gui Ye
- Department of Breast Surgery, Key Laboratory of Breast Cancer, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Jie Zhang
- Department of Breast Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou, People's Republic of China,
| | - Jun-Jing Li
- Department of Breast Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou, People's Republic of China,
| | - Qing-Xia Chen
- Department of Breast Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou, People's Republic of China,
| | - Pei-Yang Lin
- Department of Breast Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou, People's Republic of China,
| | - Chuan-Gui Song
- Department of Breast Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou, People's Republic of China,
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20
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Nicolini A, Ferrari P, Duffy MJ. Prognostic and predictive biomarkers in breast cancer: Past, present and future. Semin Cancer Biol 2018; 52:56-73. [DOI: 10.1016/j.semcancer.2017.08.010] [Citation(s) in RCA: 209] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 08/14/2017] [Accepted: 08/24/2017] [Indexed: 12/19/2022]
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21
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Pasculli B, Barbano R, Parrella P. Epigenetics of breast cancer: Biology and clinical implication in the era of precision medicine. Semin Cancer Biol 2018; 51:22-35. [PMID: 29339244 DOI: 10.1016/j.semcancer.2018.01.007] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 12/15/2017] [Accepted: 01/11/2018] [Indexed: 02/09/2023]
Abstract
In the last years, mortality from breast cancer has declined in western countries as a consequence of a more widespread screening resulting in earlier detection, as well as an improved molecular classification and advances in adjuvant treatment. Nevertheless, approximately one third of breast cancer patients will develop distant metastases and eventually die for the disease. There is now a compelling body of evidence suggesting that epigenetic modifications comprising DNA methylation and chromatin remodeling play a pivotal role since the early stages of breast cancerogenesis. In addition, recently, increasing emphasis is being placed on the property of ncRNAs to finely control gene expression at multiple levels by interacting with a wide array of molecules such that they might be designated as epigenetic modifiers. In this review, we summarize the current knowledge about the involvement of epigenetic modifications in breast cancer, and provide an overview of the significant association of epigenetic traits with the breast cancer clinicopathological features, emphasizing the potentiality of epigenetic marks to become biomarkers in the context of precision medicine.
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Affiliation(s)
- Barbara Pasculli
- Laboratory of Oncology, IRCCS "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo, FG, Italy.
| | - Raffaela Barbano
- Laboratory of Oncology, IRCCS "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo, FG, Italy.
| | - Paola Parrella
- Laboratory of Oncology, IRCCS "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo, FG, Italy.
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22
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Abstract
The accuracy and efficiency of tumor treatment depends mainly on early and precise diagnosis. Although histopathology is always the gold standard for cancer diagnosis, noninvasive biomarkers represent an opportunity for early detection and molecular staging of cancer. Besides the classical tumor markers, noncoding RNAs (ncRNAs) emerge to be a novel category of biomarker for cancer diagnosis since the dysregulation of ncRNAs is closely associated with the development and progression of human cancers such as liver, lung, breast, gastric, and other kinds of cancers. In this chapter, we will summarize the different types of ncRNAs in the diagnosis of major human cancers. In addition, we will introduce the recent advances in the detection and applications of circulating serum or plasma ncRNAs and non-blood fluid ncRNAs because the noninvasive body fluid-based assays are easy to examine for cancer diagnosis and monitoring.
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23
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Gozuacik D, Akkoc Y, Ozturk DG, Kocak M. Autophagy-Regulating microRNAs and Cancer. Front Oncol 2017; 7:65. [PMID: 28459042 PMCID: PMC5394422 DOI: 10.3389/fonc.2017.00065] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 03/21/2017] [Indexed: 12/12/2022] Open
Abstract
Macroautophagy (autophagy herein) is a cellular stress response and a survival pathway that is responsible for the degradation of long-lived proteins, protein aggregates, as well as damaged organelles in order to maintain cellular homeostasis. Consequently, abnormalities of autophagy are associated with a number of diseases, including Alzheimers’s disease, Parkinson’s disease, and cancer. According to the current view, autophagy seems to serve as a tumor suppressor in the early phases of cancer formation, yet in later phases, autophagy may support and/or facilitate tumor growth, spread, and contribute to treatment resistance. Therefore, autophagy is considered as a stage-dependent dual player in cancer. microRNAs (miRNAs) are endogenous non-coding small RNAs that negatively regulate gene expression at a post-transcriptional level. miRNAs control several fundamental biological processes, and autophagy is no exception. Furthermore, accumulating data in the literature indicate that dysregulation of miRNA expression contribute to the mechanisms of cancer formation, invasion, metastasis, and affect responses to chemotherapy or radiotherapy. Therefore, considering the importance of autophagy for cancer biology, study of autophagy-regulating miRNA in cancer will allow a better understanding of malignancies and lead to the development of novel disease markers and therapeutic strategies. The potential to provide study of some of these cancer-related miRNAs were also implicated in autophagy regulation. In this review, we will focus on autophagy, miRNA, and cancer connection, and discuss its implications for cancer biology and cancer treatment.
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Affiliation(s)
- Devrim Gozuacik
- Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.,Center of Excellence for Functional Surfaces and Interfaces for Nano Diagnostics (EFSUN), Sabanci University, Istanbul, Turkey
| | - Yunus Akkoc
- Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey
| | - Deniz Gulfem Ozturk
- Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey
| | - Muhammed Kocak
- Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey
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24
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Li CY, Xiong DD, Huang CQ, He RQ, Liang HW, Pan DH, Wang HL, Wang YW, Zhu HW, Chen G. Clinical Value of miR-101-3p and Biological Analysis of its Prospective Targets in Breast Cancer: A Study Based on The Cancer Genome Atlas (TCGA) and Bioinformatics. Med Sci Monit 2017; 23:1857-1871. [PMID: 28416776 PMCID: PMC5404822 DOI: 10.12659/msm.900030] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background MiR-101-3p can promote apoptosis and inhibit proliferation, invasion, and metastasis in breast cancer (BC) cells. However, its mechanisms in BC are not fully understood. Therefore, a comprehensive analysis of the target genes, pathways, and networks of miR-101-3p in BC is necessary. Material/Methods The miR-101 profiles for 781 patients with BC from The Cancer Genome Atlas (TCGA) were analyzed. Gene expression profiling of GSE31397 with miR-101-3p transfected MCF-7 cells and scramble control cells was downloaded from Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) were identified. The potential genes targeted by miR-101-3p were also predicted. Gene Ontology (GO) and pathway and network analyses were constructed for the DEGs and predicted genes. Results In the TCGA data, a low level of miR-101-2 expression might represent a diagnostic (AUC: 0.63) marker, and the miR-101-1 was a prognostic (HR=1.79) marker. MiR-101-1 was linked to the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), and miR-101-2 was associated with the tumor (T), lymph node (N), and metastasis (M) stages of BC. Moreover, 427 genes were selected from the 921 DEGs in GEO and the 7924 potential target genes from the prediction databases. These genes were related to transcription, metabolism, biosynthesis, and proliferation. The results were also significantly enriched in the VEGF, mTOR, focal adhesion, Wnt, and chemokine signaling pathways. Conclusions MiR-101-1 and miR-101-2 may be prospective biomarkers for the prognosis and diagnosis of BC, respectively, and are associated with diverse clinical parameters. The target genes of miR-101-3p regulate the development and progression of BC. These results provide insight into the pathogenic mechanism and potential therapies for BC.
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Affiliation(s)
- Chun-Yao Li
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Dan-Dan Xiong
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Chun-Qin Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Rong-Quan He
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Hai-Wei Liang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Deng-Hua Pan
- Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Han-Lin Wang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Yi-Wen Wang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Hua-Wei Zhu
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
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Sansone P, Berishaj M, Rajasekhar VK, Ceccarelli C, Chang Q, Strillacci A, Savini C, Shapiro L, Bowman RL, Mastroleo C, De Carolis S, Daly L, Benito-Martin A, Perna F, Fabbri N, Healey JH, Spisni E, Cricca M, Lyden D, Bonafé M, Bromberg J. Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles. Cancer Res 2017; 77:1927-1941. [PMID: 28202520 PMCID: PMC5392366 DOI: 10.1158/0008-5472.can-16-2129] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 01/12/2017] [Accepted: 01/12/2017] [Indexed: 12/12/2022]
Abstract
The hypothesis that microvesicle-mediated miRNA transfer converts noncancer stem cells into cancer stem cells (CSC) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how microvesicles derived from cancer-associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived microvesicles horizontally transferred miR-221 to tumor cells and, in combination with hormone therapy, activated an ERlo/Notchhi feed-forward loop responsible for the generation of CD133hi CSCs. Importantly, microvesicles from patients with HTR metastatic disease expressed high levels of miR-221. We further determined that the IL6-pStat3 pathway promoted the biogenesis of onco-miR-221hi CAF microvesicles and established stromal CSC niches in experimental and patient-derived breast cancer models. Coinjection of patient-derived CAFs from bone metastases led to de novo HTR tumors, which was reversed with IL6R blockade. Finally, we generated patient-derived xenograft (PDX) models from patient-derived HTR bone metastases and analyzed tumor cells, stroma, and microvesicles. Murine and human CAFs were enriched in HTR tumors expressing high levels of CD133hi cells. Depletion of murine CAFs from PDX restored sensitivity to HT, with a concurrent reduction of CD133hi CSCs. Conversely, in models of CD133neg, HT-sensitive cancer cells, both murine and human CAFs promoted de novo HT resistance via the generation of CD133hi CSCs that expressed low levels of estrogen receptor alpha. Overall, our results illuminate how microvesicle-mediated horizontal transfer of genetic material from host stromal cells to cancer cells triggers the evolution of therapy-resistant metastases, with potentially broad implications for their control. Cancer Res; 77(8); 1927-41. ©2017 AACR.
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Affiliation(s)
- Pasquale Sansone
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marjan Berishaj
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Claudio Ceccarelli
- Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, Università di Bologna, Bologna, Italy
| | - Qing Chang
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Antonio Strillacci
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Biological, Geological and Environmental Sciences, Università di Bologna, Bologna, Italy
| | - Claudia Savini
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, Università di Bologna, Bologna, Italy
- Center for Applied Biomedical Research Laboratory, Policlinico Universitario S. Orsola-Malpighi AlmaMater Studiorum, Università di Bologna, Bologna, Italy
| | - Lauren Shapiro
- Department of Radiation Oncology, Kaiser Permanente, Oakland, California
| | - Robert L Bowman
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Chiara Mastroleo
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sabrina De Carolis
- Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, Università di Bologna, Bologna, Italy
- Center for Applied Biomedical Research Laboratory, Policlinico Universitario S. Orsola-Malpighi AlmaMater Studiorum, Università di Bologna, Bologna, Italy
| | - Laura Daly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Alberto Benito-Martin
- Department of Pediatrics, Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Weill Cornell Medicine, New York, New York
| | - Fabiana Perna
- Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nicola Fabbri
- Orthopedics Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - John H Healey
- Orthopedics Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Enzo Spisni
- Department of Biological, Geological and Environmental Sciences, Università di Bologna, Bologna, Italy
| | - Monica Cricca
- Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, Università di Bologna, Bologna, Italy
| | - David Lyden
- Department of Pediatrics, Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Weill Cornell Medicine, New York, New York
- Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Massimiliano Bonafé
- Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, Università di Bologna, Bologna, Italy
- Department of Radiation Oncology, Kaiser Permanente, Oakland, California
| | - Jacqueline Bromberg
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
- Department of Medicine, Weill Cornell Medicine, New York, New York
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26
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O'Brien KP, Ramphul E, Howard L, Gallagher WM, Malone C, Kerin MJ, Dwyer RM. Circulating MicroRNAs in Cancer. Methods Mol Biol 2017; 1509:123-139. [PMID: 27826923 DOI: 10.1007/978-1-4939-6524-3_12] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
It is believed that microRNAs have potential as circulating biomarkers of disease; however, successful clinical implementation remains a challenge. This chapter highlights broad variations in approaches to microRNA analysis where whole blood, serum and plasma have each been employed as viable sources. Further discrepancies in approaches are seen in endogenous controls and extraction methods utilized. This has resulted in contradictory publications, even when the same microRNA is targeted in the same disease setting.Analysis of blood samples highlighted the impact of both collection method and storage, on the microRNA profile. Analysis of a panel of microRNAs across whole blood, serum, and plasma originating from the same individual emphasized the impact of starting material on microRNA profile. This is a highly topical field of research with immense potential for translation into the clinical setting. Standardization of sample harvesting, processing and analysis will be key to this translation. Methods of sample harvesting, preservation, and analysis are outlined, with important mitigating factors highlighted.
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Affiliation(s)
- Killian P O'Brien
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland
| | - Eimear Ramphul
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland
| | - Linda Howard
- Regenerative Medicine Institute, National University of Ireland Galway, Galway, Ireland
| | - William M Gallagher
- Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland
| | - Carmel Malone
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland
| | - Michael J Kerin
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland
| | - Róisín M Dwyer
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland.
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27
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Nassar FJ, Nasr R, Talhouk R. MicroRNAs as biomarkers for early breast cancer diagnosis, prognosis and therapy prediction. Pharmacol Ther 2016; 172:34-49. [PMID: 27916656 DOI: 10.1016/j.pharmthera.2016.11.012] [Citation(s) in RCA: 151] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Breast cancer is a major health problem that affects one in eight women worldwide. As such, detecting breast cancer at an early stage anticipates better disease outcome and prolonged patient survival. Extensive research has shown that microRNA (miRNA) are dysregulated at all stages of breast cancer. miRNA are a class of small noncoding RNA molecules that can modulate gene expression and are easily accessible and quantifiable. This review highlights miRNA as diagnostic, prognostic and therapy predictive biomarkers for early breast cancer with an emphasis on the latter. It also examines the challenges that lie ahead in their use as biomarkers. Noteworthy, this review addresses miRNAs reported in patients with early breast cancer prior to chemotherapy, radiotherapy, surgical procedures or distant metastasis (unless indicated otherwise). In this context, miRNA that are mentioned in this review were significantly modulated using more than one statistical test and/or validated by at least two studies. A standardized protocol for miRNA assessment is proposed starting from sample collection to data analysis that ensures comparative analysis of data and reproducibility of results.
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Affiliation(s)
- Farah J Nassar
- Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon
| | - Rihab Nasr
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
| | - Rabih Talhouk
- Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon.
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28
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MiR-106a: Promising biomarker for cancer. Bioorg Med Chem Lett 2016; 26:5373-5377. [PMID: 27780637 DOI: 10.1016/j.bmcl.2016.10.042] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 09/23/2016] [Accepted: 10/13/2016] [Indexed: 12/19/2022]
Abstract
MicroRNAs (miRNAs), which are characterized by highly conserved and small non-coding RNAs, have been a hot spot regarding biological processes such as cellular proliferation, apoptosis and metabolism as well as cellular differentiation, signal transduction and carcinogenesis. MiRNA-106a (miR-106a), a member of the miR-17 family, has been validated to be aberrantly regulated in the diversity of tumors. The purpose of this review is supposed to deliver an intricate overview of miR-106a, including its role in cell proliferation, apoptosis, cell cycle, invasion and metastasis, involvement in drug resistance as well as its interactions with the target proteins and signaling pathways involved.
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29
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Amorim M, Salta S, Henrique R, Jerónimo C. Decoding the usefulness of non-coding RNAs as breast cancer markers. J Transl Med 2016; 14:265. [PMID: 27629831 PMCID: PMC5024523 DOI: 10.1186/s12967-016-1025-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 08/31/2016] [Indexed: 12/19/2022] Open
Abstract
Although important advances in the management of breast cancer (BC) have been recently accomplished, it still constitutes the leading cause of cancer death in women worldwide. BC is a heterogeneous and complex disease, making clinical prediction of outcome a very challenging task. In recent years, gene expression profiling emerged as a tool to assist in clinical decision, enabling the identification of genetic signatures that better predict prognosis and response to therapy. Nevertheless, translation to routine practice has been limited by economical and technical reasons and, thus, novel biomarkers, especially those requiring non-invasive or minimally invasive collection procedures, while retaining high sensitivity and specificity might represent a significant development in this field. An increasing amount of evidence demonstrates that non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are aberrantly expressed in several cancers, including BC. miRNAs are of particular interest as new, easily accessible, cost-effective and non-invasive tools for precise management of BC patients because they circulate in bodily fluids (e.g., serum and plasma) in a very stable manner, enabling BC assessment and monitoring through liquid biopsies. This review focus on how ncRNAs have the potential to answer present clinical needs in the personalized management of patients with BC and comprehensively describes the state of the art on the role of ncRNAs in the diagnosis, prognosis and prediction of response to therapy in BC.
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Affiliation(s)
- Maria Amorim
- Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPOPorto), Research Center-LAB 3, F Bdg, 1st floor, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Porto, Portugal
| | - Sofia Salta
- Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPOPorto), Research Center-LAB 3, F Bdg, 1st floor, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Porto, Portugal
| | - Rui Henrique
- Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPOPorto), Research Center-LAB 3, F Bdg, 1st floor, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto, Porto, Portugal.,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Porto, Portugal
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPOPorto), Research Center-LAB 3, F Bdg, 1st floor, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal. .,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Porto, Portugal.
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30
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Cappelletti V, Appierto V, Tiberio P, Fina E, Callari M, Daidone MG. Circulating Biomarkers for Prediction of Treatment Response. J Natl Cancer Inst Monogr 2016; 2015:60-3. [PMID: 26063889 DOI: 10.1093/jncimonographs/lgv006] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
For cancer management, predicting and monitoring response to treatment and disease progression longitudinally is crucial due to changes in tumor biology and therapy responsiveness over time. However, solid tumors are usually sampled only at time of initial diagnosis, as obtaining tissue biopsies is an invasive procedures with associated risks. Thus, there is a pressing need for approaches able to serially detect function-related reliable biomarkers reflecting treatment response and/or disease progression through easy noninvasive procedures, amenable for longitudinal analysis of tumor molecular features. Recent evidences indicate that blood and other body fluids could replace invasive surgical biopsies and represent a "liquid biopsy" containing cells and nucleic acids released by primary and metastatic lesions, reflecting their biological features and allowing identification of clinically useful biomarkers and treatment-induced cancer adaption processes. The development of new and highly sensitive technologies that allow to detect and characterize circulating tumor cells, to identify cell-free nucleic acids (circulating tumor-associated microRNAs and cancer-specific mutations in circulating DNA) and to measure their eventual dynamic changes represents therefore a major achievement for disease monitoring. However, notwithstanding preliminary findings support the prognostic and/or predictive role of this new generation of biomarkers, there are a number of technical and biological caveats that still require additional studies to demonstrate and validate their clinical utility. A unique opportunity to rapidly assess the contribution of circulating tumor cells and cell-free nucleic acids to patient management and to personalized medicine could derive by their combined consideration in the neoadjuvant setting.
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Affiliation(s)
- Vera Cappelletti
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (VC, VA, PT, EF, MC, MGD)
| | - Valentina Appierto
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (VC, VA, PT, EF, MC, MGD)
| | - Paola Tiberio
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (VC, VA, PT, EF, MC, MGD)
| | - Emanuela Fina
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (VC, VA, PT, EF, MC, MGD)
| | - Maurizio Callari
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (VC, VA, PT, EF, MC, MGD)
| | - Maria Grazia Daidone
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (VC, VA, PT, EF, MC, MGD).
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31
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Casey MC, Sweeney KJ, Brown JAL, Kerin MJ. Exploring circulating micro-RNA in the neoadjuvant treatment of breast cancer. Int J Cancer 2016; 139:12-22. [PMID: 26756433 PMCID: PMC5066681 DOI: 10.1002/ijc.29985] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 11/04/2015] [Accepted: 12/22/2015] [Indexed: 12/18/2022]
Abstract
Breast cancer is the most frequently diagnosed malignancy amongst females worldwide. In recent years the management of this disease has transformed considerably, including the administration of chemotherapy in the neoadjuvant setting. Aside from increasing rates of breast conserving surgery and enabling surgery via tumour burden reduction, use of chemotherapy in the neoadjuvant setting allows monitoring of in vivo tumour response to chemotherapeutics. Currently, there is no effective means of identifying chemotherapeutic responders from non‐responders. Whilst some patients achieve complete pathological response (pCR) to chemotherapy, a good prognostic index, a proportion of patients derive little or no benefit, being exposed to the deleterious effects of systemic treatment without any knowledge of whether they will receive benefit. The identification of predictive and prognostic biomarkers could confer multiple benefits in this setting, specifically the individualization of breast cancer management and more effective administration of chemotherapeutics. In addition, biomarkers could potentially expedite the identification of novel chemotherapeutic agents or increase their efficacy. Micro‐RNAs (miRNAs) are small non‐coding RNA molecules. With their tissue‐specific expression, correlation with clinicopathological prognostic indices and known dysregulation in breast cancer, miRNAs have quickly become an important avenue in the search for novel breast cancer biomarkers. We provide a brief history of breast cancer chemotherapeutics and explore the emerging field of circulating (blood‐borne) miRNAs as breast cancer biomarkers for the neoadjuvant treatment of breast cancer. Established molecular markers of breast cancer are outlined, while the potential role of circulating miRNAs as chemotherapeutic response predictors, prognosticators or potential therapeutic targets is discussed.
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Affiliation(s)
- Máire-Caitlín Casey
- Discipline of Surgery, School of Medicine, National University of Ireland, Galway, Ireland
| | - Karl J Sweeney
- Discipline of Surgery, School of Medicine, National University of Ireland, Galway, Ireland
| | | | - Michael J Kerin
- Discipline of Surgery, School of Medicine, National University of Ireland, Galway, Ireland
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32
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Vychytilova-Faltejskova P, Slaby O. Circulating Blood-Borne microRNAs as Biomarkers in Solid Tumors. ACTA ACUST UNITED AC 2015; 106:75-122. [PMID: 26608200 DOI: 10.1007/978-3-0348-0955-9_4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
One of the major challenges in cancer research is the identification of stable biomarkers that could be routinely measured in easily accessible samples. Human blood and other body fluids represent rich sources for the identification of novel biomarkers. It is apparent that the availability of these biomarkers would improve an early detection of asymptomatic disease and the clinical management of cancer. MicroRNAs have been described to be present in various types of body fluids including cell-free serum and plasma. These days, the involvement of microRNAs in molecular pathology of cancer is well established. Moreover, it seems that these molecules could be optimal noninvasive biomarkers owing to their high stability under storage and handling conditions and high sensitivity and specificity in various diseases. To date, more than 100 circulating microRNAs with the potential to serve as novel diagnostic, prognostic, or predictive biomarkers for different types of cancers have been identified, and this number is still increasing. However, there are major discrepancies in the findings by different research groups, and few commonly altered microRNAs have been reported in these studies. Further studies on large cohorts using uniform methodology are warranted to establish the clinical applicability of circulating microRNAs for solid tumors. Here, we summarize the tumor-specific profiles of blood-borne microRNAs and discuss their potential utility for personalized medicine of solid tumors.
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Affiliation(s)
| | - Ondrej Slaby
- Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.
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Sun C, Sang M, Li S, Sun X, Yang C, Xi Y, Wang L, Zhang F, Bi Y, Fu Y, Li D. Hsa-miR-139-5p inhibits proliferation and causes apoptosis associated with down-regulation of c-Met. Oncotarget 2015; 6:39756-92. [PMID: 26497851 PMCID: PMC4741860 DOI: 10.18632/oncotarget.5476] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 10/07/2015] [Indexed: 01/01/2023] Open
Abstract
Hsa-miRNA-139-5p (miR-139-5p) has recently been discovered having anticancer efficacy in different organs. However, the role of miR-139-5p on lung cancer is still ambiguous. In this study, we investigated the role of miR-139-5p on development of lung cancer. Results indicated miR-139-5p was significantly down-regulated in primary tumor tissues and very low levels were found in a non-small cell lung cancer (NSCLC) cell lines. Ectopic expression of miR-139-5p in NSCLC cell lines significantly suppressed cell growth through inhibition of cyclin D1 and up-regulation of p57(Kip2). In addition, miR-139-5p induced apoptosis, as indicated by up-regulation of key apoptosis gene cleaved caspase-3, and down-regulation of anti-apoptosis gene Bcl2. Moreover, miR-139-5p inhibited cellular metastasis through inhibition of matrix metalloproteinases (MMP)-7 and MMP-9. Further, oncogene c-Met was revealed to be a putative target of miR-139-5p, which was inversely correlated with miR-139-5p expression. Taken together, our results demonstrated that miR-139-5p plays a pivotal role in lung cancer through inhibiting cell proliferation, metastasis, and promoting apoptosis by targeting oncogenic c-Met.
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Affiliation(s)
- Chengcao Sun
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China
- Institute of Global Health, Wuhan University, 430071 Wuhan, P. R. China
| | - Ming Sang
- Central Laboratory of the Fourth Affiliated Hospital in Xiangyang, College of Basic Medical Sciences, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, 442000 Shiyan, P. R. China
| | - Shujun Li
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China
- Wuhan Hospital for the Prevention and Treatment of Occupational Diseases, 430071 Wuhan, P. R. China
| | - Xiaodong Sun
- Central Laboratory of the Fourth Affiliated Hospital in Xiangyang, College of Basic Medical Sciences, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, 442000 Shiyan, P. R. China
| | - Cuili Yang
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China
| | - Yongyong Xi
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China
| | - Liang Wang
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China
| | - Feng Zhang
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China
| | - Yongyi Bi
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China
| | - Yunfeng Fu
- The Third Xiang-ya Hospital of Central South University, 410013 Changsha, P. R. China
| | - Dejia Li
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China
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34
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RBMMMDA: predicting multiple types of disease-microRNA associations. Sci Rep 2015; 5:13877. [PMID: 26347258 PMCID: PMC4561957 DOI: 10.1038/srep13877] [Citation(s) in RCA: 124] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 08/07/2015] [Indexed: 12/20/2022] Open
Abstract
Accumulating evidences have shown that plenty of miRNAs play fundamental and important roles in various biological processes and the deregulations of miRNAs are associated with a broad range of human diseases. However, the mechanisms underlying the dysregulations of miRNAs still have not been fully understood yet. All the previous computational approaches can only predict binary associations between diseases and miRNAs. Predicting multiple types of disease-miRNA associations can further broaden our understanding about the molecular basis of diseases in the level of miRNAs. In this study, the model of Restricted Boltzmann machine for multiple types of miRNA-disease association prediction (RBMMMDA) was developed to predict four different types of miRNA-disease associations. Based on this model, we could obtain not only new miRNA-disease associations, but also corresponding association types. To our knowledge, RBMMMDA is the first model which could computationally infer association types of miRNA-disease pairs. Leave-one-out cross validation was implemented for RBMMMDA and the AUC of 0.8606 demonstrated the reliable and effective performance of RBMMMDA. In the case studies about lung cancer, breast cancer, and global prediction for all the diseases simultaneously, 50, 42, and 45 out of top 100 predicted miRNA-disease association types were confirmed by recent biological experimental literatures, respectively.
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35
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Sisic L, Vallböhmer D, Stoecklein NH, Blank S, Schmidt T, Driemel C, Möhlendick B, Knoefel WT, Odenthal M, Ott K. Serum microRNA profiles as prognostic or predictive markers in the multimodality treatment of patients with gastric cancer. Oncol Lett 2015; 10:869-874. [PMID: 26622585 DOI: 10.3892/ol.2015.3341] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2014] [Accepted: 02/27/2015] [Indexed: 12/22/2022] Open
Abstract
Despite the implementation of multimodality treatment strategies, the persistently poor prognosis of gastric cancer patients is predominantly caused by the lack of predictive markers for response assessment in the neoadjuvant setting, preventing individualized therapy. Therefore, the identification of novel predictive and prognostic markers for application in the multimodality treatment of gastric cancer patients is required. The aim of the present study was to characterize the serum microRNA (miRNA/miR) profile of gastric cancer patients undergoing multimodality therapy to identify possible prognostic and predictive markers. The study consisted of 32 patients with gastric cancer who had undergone either primary surgical resection (n=14) or neoadjuvant therapy followed by surgical resection (n=18). Histopathological regression was defined as a major histopathological response when the resected specimens contained <10% vital residual tumor cells. Intratumoral miRNA was isolated from pre-operative or post-neoadjuvant blood serum samples. Initially, microarray analyses were performed in six of the patients that received neoadjuvant treatment (three responders versus three non-responders), to assess the amplification profile of dysregulated miRNAs. Based on these findings, possible predictive or prognostic markers were validated in all study patients by performing single reverse transcription-polymerase chain reaction (RT-PCR) analysis. Depending on the extent of the histopathological regression, a differential miRNA expression profile was identified in the microarray analyses. Based on the amplification profile, miR-21, miR-29a and miR-221 were selected for additional validation. However, the single RT-PCR measurements of the three selected miRNAs did not exhibit any prognostic or predictive value in the patients treated with primary resection or neoadjuvant therapy and resection. Thus, the current pilot study failed to identify a prognostic or predictive value in selected miRNAs using single RT-PCR measurements, however, the microarray results revealed a differential microRNA expression profile depending on the histopathological regression. The findings of the present study may have been affected by the small sample size.
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Affiliation(s)
- Leila Sisic
- Department of General, Visceral, Pediatric and Vascular Surgery, University of Heidelberg, Heidelberg D-69115, Germany
| | - Daniel Vallböhmer
- Department of General, Visceral and Pediatric Surgery, University of Düsseldorf, Düsseldorf D-40225, Germany
| | - Nikolas H Stoecklein
- Department of General, Visceral and Pediatric Surgery, University of Düsseldorf, Düsseldorf D-40225, Germany
| | - Susanne Blank
- Department of General, Visceral, Pediatric and Vascular Surgery, University of Heidelberg, Heidelberg D-69115, Germany
| | - Thomas Schmidt
- Department of General, Visceral, Pediatric and Vascular Surgery, University of Heidelberg, Heidelberg D-69115, Germany
| | - Christiane Driemel
- Department of General, Visceral and Pediatric Surgery, University of Düsseldorf, Düsseldorf D-40225, Germany
| | - Birte Möhlendick
- Department of General, Visceral and Pediatric Surgery, University of Düsseldorf, Düsseldorf D-40225, Germany
| | - Wolfram T Knoefel
- Department of General, Visceral and Pediatric Surgery, University of Düsseldorf, Düsseldorf D-40225, Germany
| | | | - Katja Ott
- Department of General, Visceral, Pediatric and Vascular Surgery, University of Heidelberg, Heidelberg D-69115, Germany
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36
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Yang S, Yang Y. Downregulation of microRNA‑221 decreases migration and invasion in fibroblast‑like synoviocytes in rheumatoid arthritis. Mol Med Rep 2015; 12:2395-401. [PMID: 25891943 DOI: 10.3892/mmr.2015.3642] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2014] [Accepted: 03/24/2015] [Indexed: 11/06/2022] Open
Abstract
MicroRNAs (miRNAs/miRs) are a group of non-coding RNAs that regulate the activity of target mRNAs and cellular processes, and which have been implicated in the pathogenesis of autoimmune diseases. miR-221 is one of the miRNAs that regulate cell proliferation, invasion and apoptosis in tumors. However, the role of miR-221 in rheumatoid arthritis (RA) remains to be fully elucidated. Therefore, the present study was undertaken to identify the role of miR-221 in RA. The expression of miR-221 in serum and synovial tissues of patients with RA and healthy controls was confirmed by reverse transcription quantitative polymerase chain reaction analysis. The effects of miR-221 on pro-inflammatory cytokines and a chemokine were assessed by ELISA. The effects of miR-221 on cell apoptosis, migration and invasion in fibroblast-like synoviocytes (FLS) were also assessed in vitro. The results showed that miR-221 expression in serum and synovial tissues of patients with RA was higher than that in healthy controls. Downregulation of miR-221 significantly suppressed the expression of pro-inflammatory cytokines and the chemokine, and inhibited FLS cell migration and invasion via inhibiting vascular endothelial growth factor, matrix metalloproteinase (MMP)-3 and MMP-9 expression. In addition, downregulation of miR-221 significantly induced cell apoptosis and decreased survivin and X-linked inhibitor of apoptosis protein expression. These findings indicated that downregulation of miR-221 inhibited the expression of pro-inflammatory cytokines and the chemokine, suppressed FLS cell migration and invasion, and induced cell apoptosis. Therefore, miR-221 is likely to be implicated in RA pathogenesis via these mechanisms, and may be a target for the treatment of RA.
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Affiliation(s)
- Shuzhong Yang
- Department of Orthopaedics, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Yougeng Yang
- Department of Orthopaedics, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
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Zhang HD, Jiang LH, Sun DW, Li J, Tang JH. MiR-139-5p: promising biomarker for cancer. Tumour Biol 2015; 36:1355-65. [DOI: 10.1007/s13277-015-3199-3] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 01/30/2015] [Indexed: 12/22/2022] Open
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Wu X, Zeng R, Wu S, Zhong J, Yang L, Xu J. Comprehensive expression analysis of miRNA in breast cancer at the miRNA and isomiR levels. Gene 2014; 557:195-200. [PMID: 25523096 DOI: 10.1016/j.gene.2014.12.030] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Revised: 12/09/2014] [Accepted: 12/14/2014] [Indexed: 12/21/2022]
Abstract
Breast cancer (BC) is the main factor that leads cause of cancer death in women worldwide. A class of small non-coding RNAs, microRNAs (miRNAs), has been widely studied in human cancers as crucial regulatory molecule. Recent studies indicate that a series of isomiRs can be yielded from a miRNA locus, and these physiological miRNA isoforms have versatile roles in miRNA biogenesis. Herein, we performed a comprehensive analysis of miRNAs at the miRNA and isomiR levels in BC using next-generation sequencing data from The Cancer Genome Atlas (TCGA). Abnormally expressed miRNA (miR-21, miR-221, miR-155, miR-30e and miR-25) and isomiR profiles could be obtained at the miRNA and isomiR levels, and similar biological roles could be detected. IsomiR expression profiles should be further concerned, and especially isomiRs are actual regulatory molecules in the miRNA-mRNA regulatory networks. The study provides a comprehensive expression analysis at the miRNA and isomiR levels in BC, which indicates biological roles of isomiRs.
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Affiliation(s)
- Xianjin Wu
- The First Affiliated Hospital of Jinan University, Guangzhou 510630, China; Department of Clinical Laboratory, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China
| | - Rong Zeng
- Orthopedic Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China
| | - Shaoke Wu
- Orthopedic Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China
| | - Jixin Zhong
- Oncology Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China
| | - Lawei Yang
- Clinical Research Center, Guangdong Medical College, Zhanjiang, Guangdong 524001, China
| | - Junfa Xu
- Institute of Laboratory Medicine, Guangdong Medical College, Dongguan 523808, China; Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Dongguan 523808, China.
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Mulrane L, Klinger R, McGee SF, Gallagher WM, O'Connor DP. microRNAs: a new class of breast cancer biomarkers. Expert Rev Mol Diagn 2014; 14:347-63. [PMID: 24649821 DOI: 10.1586/14737159.2014.901153] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
MicroRNAs (miRNAs) are regulatory molecules known to be aberrantly expressed in cancer and contribute to numerous aspects of tumor biology including the initiation, growth and spread of the tumor. With such diverse roles, it is becoming apparent that some may also provide valuable information which may be of use in a clinical setting, demonstrating the potential to act as both screening tools for the stratification of high-risk patients, while informing the treatment decision-making process. There is mounting evidence to suggest that some miRNAs may even provide assistance in the diagnosis of patients with breast cancer. In addition, miRNAs may themselves be considered therapeutic targets, with inhibition or reintroduction of a particular miRNA capable of inducing a response in vivo. This review focuses on miRNAs that have prognostic, diagnostic or predictive potential in breast cancer as well as the possible challenges in the translation of such observations to the clinic.
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Affiliation(s)
- Laoighse Mulrane
- UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
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40
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Xue J, Niu J, Wu J, Wu ZH. MicroRNAs in cancer therapeutic response: Friend and foe. World J Clin Oncol 2014; 5:730-743. [PMID: 25302173 PMCID: PMC4129536 DOI: 10.5306/wjco.v5.i4.730] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2014] [Revised: 03/15/2014] [Accepted: 06/18/2014] [Indexed: 02/06/2023] Open
Abstract
Cancer initiation and development engage extremely complicated pathological processes which involve alterations of a large number of cell signaling cascades and functional networks in temporal and spatial orders. During last decades, microRNAs (miRNAs), a class of non-coding RNAs, have emerged as critical players in cancer pathogenesis and progression by modulating many pathological aspects related to tumor development, growth, metastasis, and drug resistance. The major function of miRNAs is to post-transcriptionally regulate gene expression depending on recognition of complementary sequence residing in target mRNAs. Commonly, a particular miRNA recognition sequence could be found in a number of genes, which allows a single miRNA to regulate multiple functionally connected genes simultaneously and/or chronologically. Furthermore, a single gene can be targeted and regulated by multiple miRNAs. However, previous studies have demonstrated that miRNA functions are highly context-dependent, which leads to distinct pathological outcomes in different types of cancer as well as at different stages by alteration of the same miRNA. Here we summarize recent progress in studies on miRNA function in cancer initiation, metastasis and therapeutic response, focusing on breast cancer. The varying functions of miRNAs and potential application of using miRNAs as biomarkers as well as therapeutic approaches are further discussed in the context of different cancers.
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Jiao Q, Wu A, Shao G, Peng H, Wang M, Ji S, Liu P, Zhang J. The latest progress in research on triple negative breast cancer (TNBC): risk factors, possible therapeutic targets and prognostic markers. J Thorac Dis 2014; 6:1329-35. [PMID: 25276378 DOI: 10.3978/j.issn.2072-1439.2014.08.13] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Accepted: 07/28/2014] [Indexed: 12/28/2022]
Abstract
Triple negative breast cancer (TNBC) is one type of breast cancer (BC), which is defined as negative for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (Her2). Its origins and development seem to be elusive. And for now, drugs like tamoxifen or trastuzumab which specifically apply to ER, PR or Her2 positive BC seem unforeseeable in TNBC clinical treatment. Due to its extreme malignancy, high recurrence rate and poor prognosis, a lot of work on the research of TNBC is needed. This review aims to summarize the latest findings in TNBC in risk factors, possible therapeutic targets and possible prognostic makers.
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Affiliation(s)
- Qingli Jiao
- 1 Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China ; 2 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China ; 3 Department of Breast Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510275, China
| | - Aiguo Wu
- 1 Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China ; 2 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China ; 3 Department of Breast Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510275, China
| | - Guoli Shao
- 1 Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China ; 2 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China ; 3 Department of Breast Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510275, China
| | - Haoyu Peng
- 1 Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China ; 2 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China ; 3 Department of Breast Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510275, China
| | - Mengchuan Wang
- 1 Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China ; 2 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China ; 3 Department of Breast Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510275, China
| | - Shufeng Ji
- 1 Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China ; 2 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China ; 3 Department of Breast Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510275, China
| | - Peng Liu
- 1 Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China ; 2 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China ; 3 Department of Breast Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510275, China
| | - Jian Zhang
- 1 Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China ; 2 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China ; 3 Department of Breast Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510275, China
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Shen J, Hu Q, Schrauder M, Yan L, Wang D, Medico L, Guo Y, Yao S, Zhu Q, Liu B, Qin M, Beckmann MW, Fasching PA, Strick R, Johnson CS, Ambrosone CB, Zhao H, Liu S. Circulating miR-148b and miR-133a as biomarkers for breast cancer detection. Oncotarget 2014; 5:5284-94. [PMID: 25051376 PMCID: PMC4170614 DOI: 10.18632/oncotarget.2014] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 05/26/2014] [Indexed: 12/14/2022] Open
Abstract
Circulating microRNAs have drawn a great deal of attention as promising novel biomarkers for breast cancer. However, to date, the results are mixed. Here, we performed a three-stage microRNA analysis using plasma samples from breast cancer patients and healthy controls, with efforts taken to address several pitfalls in detection techniques and study design observed in previous studies. In the discovery phase with 122 Caucasian study subjects, we identified 43 microRNAs differentially expressed between breast cancer cases and healthy controls. When those microRNAs were compared with published data from other studies, we identified three microRNAs, including miR-148b, miR-133a and miR-409-3p, whose plasma levels were significantly higher in breast cancer cases than healthy controls and were also significant in previous independent studies. In the validation phase with 50 breast cancer cases and 50 healthy controls, we validated the associations with breast cancer detection for miR-148b and miR-133a (P = 1.5×10-6 and 1.3×10-10, respectively). In the in-vitro study phase, we found that both miR-148b and miR-133a were secreted from breast cancer cell lines, showing their secretory potential and possible tumor origin. Thus, our data suggest that both miR-148b and miR-133a have potential use as biomarkers for breast cancer detection.
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Affiliation(s)
- Jie Shen
- Department of Epidemiology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Qiang Hu
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, P.R.China
| | - Michael Schrauder
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Dan Wang
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Leonardo Medico
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Yuqing Guo
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Song Yao
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Qianqian Zhu
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Biao Liu
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Maochun Qin
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Matthias W. Beckmann
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Peter A. Fasching
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Reiner Strick
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Candace S. Johnson
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Christine B. Ambrosone
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Hua Zhao
- Department of Epidemiology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Song Liu
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
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43
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Li Y, Liang C, Ma H, Zhao Q, Lu Y, Xiang Z, Li L, Qin J, Chen Y, Cho WC, Pestell RG, Liang L, Yu Z. miR-221/222 promotes S-phase entry and cellular migration in control of basal-like breast cancer. Molecules 2014; 19:7122-37. [PMID: 24886939 PMCID: PMC6271560 DOI: 10.3390/molecules19067122] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 05/22/2014] [Accepted: 05/26/2014] [Indexed: 12/16/2022] Open
Abstract
The miR-221/222 cluster has been demonstrated to function as oncomiR in human cancers. miR-221/222 promotes epithelial-to-mesenchymal transition (EMT) and confers tamoxifen resistance in breast cancer. However, the effects and mechanisms by which miR-221/222 regulates breast cancer aggressiveness remain unclear. Here we detected a much higher expression of miR-221/222 in highly invasive basal-like breast cancer (BLBC) cells than that in non-invasive luminal cells. A microRNA dataset from breast cancer patients indicated an elevated expression of miR-221/222 in BLBC subtype. S-phase entry of the cell cycle was associated with the induction of miR-221/222 expression. miRNA inhibitors specially targeting miR-221 or miR-222 both significantly suppressed cellular migration, invasion and G1/S transition of the cell cycle in BLBC cell types. Proteomic analysis demonstrated the down-regulation of two tumor suppressor genes, suppressor of cytokine signaling 1 (SOCS1) and cyclin-dependent kinase inhibit 1B (CDKN1B), by miR-221/222. This is the first report to reveal miR-221/222 regulation of G1/S transition of the cell cycle. These findings demonstrate that miR-221/222 contribute to the aggressiveness in control of BLBC.
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Affiliation(s)
- Yuan Li
- Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
| | - Chunli Liang
- Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
| | - Haizhong Ma
- Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
| | - Qian Zhao
- Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
| | - Ying Lu
- Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
| | - Zhendong Xiang
- Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
| | - Li Li
- Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
| | - Jie Qin
- Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai 200120, China.
| | - Yihan Chen
- Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China.
| | - Richard G Pestell
- Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
| | - Li Liang
- Lanzhou University School of Pharmacy, the First Affiliated Hospital of Lanzhou University, Lanzhou, Gansu 730000, China.
| | - Zuoren Yu
- Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
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Gezer U, Keskin S, Iğci A, Tükenmez M, Tiryakioğlu D, Cetinkaya M, Dişci R, Dalay N, Eralp Y. Abundant circulating microRNAs in breast cancer patients fluctuate considerably during neoadjuvant chemotherapy. Oncol Lett 2014; 8:845-848. [PMID: 25009660 PMCID: PMC4081437 DOI: 10.3892/ol.2014.2188] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Accepted: 05/15/2014] [Indexed: 11/30/2022] Open
Abstract
Previous studies have revealed the aberrant expression of a number of microRNAs (miRNA/miRs) in the blood circulation of patients with breast cancer (BC). The aim of the present study was to assess the effect of neoadjuvant chemotherapy on the levels of a panel of BC-associated miRNAs, which are at relatively low (let-7, miR-10b, miR-34, miR-155, miR-200c and miR-205) or abundant (miR-21, miR-195 and miR-221) levels in the circulation. Patients with primary operable or locally advanced BC were enrolled in the study. The plasma levels of the miRNAs at baseline and at the fourth cycle of treatment were compared. Patients with stage II disease exhibited higher basal miRNAs levels than those with higher stages. The difference was most evident for miR-155 and miR-21 (P=0.05). From the initial to the fourth cycle of chemotherapy, the miRNA levels changed substantially. In samples in which the miRNA levels generally declined, a marked decrease (≤15,500-fold) was evident for the abundant miRNAs. Notably, the occurrence of a decrease in miRNA levels was more frequent in patients with smaller tumor sizes (P<0.05 for miR-21 and miR-195). This proof-of-concept study provides evidence that highly expressed miRNAs are affected most frequently by chemotherapy, particularly in patients with early stage tumors. This information may be valuable in assessing the response of the patients to therapy.
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Affiliation(s)
- Ugur Gezer
- Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul 34093, Turkey
| | - Serkan Keskin
- Department of Clinical Oncology, Oncology Institute, Istanbul University, Istanbul 34093, Turkey
| | - Abdullah Iğci
- Department of General Surgery, Istanbul Medical Faculty, Istanbul University, Istanbul 34093, Turkey
| | - Mustafa Tükenmez
- Department of General Surgery, Istanbul Medical Faculty, Istanbul University, Istanbul 34093, Turkey
| | - Duygu Tiryakioğlu
- Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul 34093, Turkey
| | - Merve Cetinkaya
- Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul 34093, Turkey
| | - Rian Dişci
- Department of Clinical Oncology, Oncology Institute, Istanbul University, Istanbul 34093, Turkey
| | - Nejat Dalay
- Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul 34093, Turkey
| | - Yeşim Eralp
- Department of Clinical Oncology, Oncology Institute, Istanbul University, Istanbul 34093, Turkey
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45
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Christodoulatos GS, Dalamaga M. Micro-RNAs as clinical biomarkers and therapeutic targets in breast cancer: Quo vadis? World J Clin Oncol 2014; 5:71-81. [PMID: 24829853 PMCID: PMC4014798 DOI: 10.5306/wjco.v5.i2.71] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 02/23/2014] [Accepted: 03/17/2014] [Indexed: 02/06/2023] Open
Abstract
Breast cancer (BC) is the most frequent type of non skin cancer among women and a major leading cause of cancer-related deaths in Western countries. It is substantial to discover novel biomarkers with diagnostic, prognostic or predictive usefulness as well as therapeutic value for BC. Micro-RNAs (miRNAs) belong to a novel class of endogenous interfering RNAs that play a crucial role in post transcriptional gene silencing through mRNA targeting and, thus, are involved in many biological processes encompassing apoptosis, cell-cycle control, cell proliferation, DNA repair, immunity, metabolism, stress, aging, etc. MiRNAs exert their action mainly in a tumor suppressive or oncogenic manner. The specific aberrant expression patterns of miRNAs in BC that are detected with the use of high-throughput technologies reflect their key role in cancer initiation, progression, migration, invasion and metastasis. The detection of circulating extracellular miRNAs in plasma of BC patients may provide novel, non-invasive biomarkers in favor of BC diagnosis and prognosis and, at the same time, accumulating evidence has underscored the possible contribution of miRNAs as valuable biomarkers to predict response to chemotherapy or radiotherapy. Data from in vitro and in vivo studies on BC have revealed promising therapeutic approaches via miRNA delivery and miRNA inhibition. The purpose of this review is to explore the ontological role of miRNAs in BC etiopathogenesis as well as to highlight their potential, not only as non-invasive circulating biomarkers with diagnostic and prognostic significance, but also as treatment response predictors and therapeutic targets aiding BC management.
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Tessari A, Palmieri D, Di Cosimo S. Overview of diagnostic/targeted treatment combinations in personalized medicine for breast cancer patients. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2013; 7:1-19. [PMID: 24403841 PMCID: PMC3883531 DOI: 10.2147/pgpm.s53304] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Breast cancer includes a body of molecularly distinct subgroups, characterized by different presentation, prognosis, and sensitivity to treatments. Significant advances in our understanding of the complex architecture of this pathology have been achieved in the last few decades, thanks to new biotechnologies that have recently come into the research field and the clinical practice, giving oncologists new instruments that are based on biomarkers and allowing them to set up a personalized approach for each individual patient. Here we review the main treatments available or in preclinical development, the biomolecular diagnostic and prognostic approaches that changed our perspective about breast cancer, giving an overview of targeted therapies that represent the current standard of care for these patients. Finally, we report some examples of how new technologies in clinical practice can set in motion the development of new drugs.
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Affiliation(s)
- Anna Tessari
- Division of Medical Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Dario Palmieri
- Molecular Biology and Cancer Genetics, Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Serena Di Cosimo
- Division of Medical Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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47
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Abstract
miRNAs have emerged, in the last decade, as key players in the carcinogenic process, with many candidates identified as playing important roles in many aspects of tumor development, growth, metastasis, and drug resistance. More recently, polymorphisms in miRNAs themselves or in their binding sites in target genes have been identified to incur increased risk of breast cancer in certain populations. In addition, epigenetic regulation and differential expression of processing enzymes has been shown to contribute to the aberrant expression of miRNAs in breast cancer. This review focuses on the area of miRNA dysregulation in breast cancer through both genetic and epigenetic mechanisms, and the impact of this dysregulation on breast cancer risk and resistance to therapies.
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Affiliation(s)
- Laoighse Mulrane
- Authors' Affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland
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48
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Verburg FA, Luster M, Cupini C, Chiovato L, Duntas L, Elisei R, Feldt-Rasmussen U, Rimmele H, Seregni E, Smit JWA, Theimer C, Giovanella L. Implications of thyroglobulin antibody positivity in patients with differentiated thyroid cancer: a clinical position statement. Thyroid 2013; 23:1211-25. [PMID: 23692026 DOI: 10.1089/thy.2012.0606] [Citation(s) in RCA: 111] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Even though the presence of antithyroglobulin antibodies (TgAbs) represents a significant problem in the follow-up of patients with differentiated thyroid cancer (DTC), the current guidelines on the management of DTC that have been published in recent years contain no text concerning the methods to be used for detecting such antibody-related interference in thyroglobulin (Tg) measurement or how to manage TgAb-positive patients in whom Tg cannot be used reliably as a tumor marker. AIM An international group of experts from the European Thyroid Association Cancer Research Network who are involved in the care of DTC patients met twice to form a consensus opinion on how to proceed with treatment and follow-up in TgAb-positive DTC patients based on the available evidence in the literature. Here we will report on the consensus opinions that were reached regarding technical and clinical issues. RESULTS This clinical opinion article provides an overview of the available evidence and the resulting consensus recommendations. The current literature does not provide sufficient data for giving evidence-based answers to many questions arising in the care of TgAb-positive DTC patients. Where insufficient evidence was available, a thorough discussion by a group of physician-scientists, all of whom have a distinguished track record in thyroid cancer care, was held to arrive at a consensus expert opinion. The questions and answers discussed were then summarized into an algorithm for the management of TgAb-positive patients. CONCLUSION We were able to define 26 consensus expert recommendations and a resulting algorithm for the care of TgAb-positive DTC patients.
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Affiliation(s)
- Frederik A Verburg
- 1 Department of Nuclear Medicine, University Hospital Aachen , Aachen, Germany
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Piva R, Spandidos DA, Gambari R. From microRNA functions to microRNA therapeutics: novel targets and novel drugs in breast cancer research and treatment (Review). Int J Oncol 2013; 43:985-94. [PMID: 23939688 PMCID: PMC3829774 DOI: 10.3892/ijo.2013.2059] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Accepted: 08/12/2013] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs or miRs) are a family of small non-coding RNAs that regulate gene expression by the sequence-selective targeting of mRNAs, leading to translational repression or mRNA degradation, depending on the degree of complementarity with target mRNA sequences. miRNAs play a crucial role in cancer. In the case of breast tumors, several studies have demonstrated a correlation between: i) the expression profile of oncogenic miRNAs (oncomiRs) or tumor suppressor miRNAs and ii) the tumorigenic potential of triple-negative [estrogen receptor (ER), progesterone receptor (PR) and Her2/neu] primary breast cancers. Among the miRNAs involved in breast cancer, miR-221 plays a crucial role for the following reasons: i) miR-221 is significantly overexpressed in triple-negative primary breast cancers; ii) the oncosuppressor p27
Kip1
, a validated miR-221 target, is downregulated in aggressive cancer cell lines; and iii) the upregulation of a key transcription factor, Slug, appears to be crucial, since it binds to the miR-221/miR-222 promoter and is responsible for the high expression of the miR-221/miR-222 cluster in breast cancer cells. A Slug/miR-221 network has been suggested, linking miR-221 activity with the downregulation of a Slug repressor, leading to Slug/miR-221 upregulation and p27
Kip1
downregulation. Interference with this process can be achieved using antisense miRNA (antagomiR) molecules targeting miR-221, inducing the down-regulation of Slug and the upregulation of p27
Kip1
.
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Affiliation(s)
- Roberta Piva
- Department of Biomedical and Specialty Surgical Sciences, Ferrara University, Ferrara, Italy
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Murata K, Furu M, Yoshitomi H, Ishikawa M, Shibuya H, Hashimoto M, Imura Y, Fujii T, Ito H, Mimori T, Matsuda S. Comprehensive microRNA analysis identifies miR-24 and miR-125a-5p as plasma biomarkers for rheumatoid arthritis. PLoS One 2013; 8:e69118. [PMID: 23874885 PMCID: PMC3715465 DOI: 10.1371/journal.pone.0069118] [Citation(s) in RCA: 138] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 06/03/2013] [Indexed: 12/31/2022] Open
Abstract
MicroRNAs (miRNAs) are present in human plasma and known as a non-invasive biomarker for cancer detection. Our study was designed to identify plasma miRNAs specific for rheumatoid arthritis (RA) by a comprehensive array approach. We performed a systematic, array-based miRNA analysis on plasma samples from three RA patients and three healthy controls (HCs). Plasma miRNAs with more than four times change or with significant (P<0.05) change in expression, or detectable only in RA plasma, were confirmed with plasma from eight RA patients and eight HCs using real-time quantitative PCR. Consistently detectable miRNAs that were significantly different between RA patients and HCs were chosen for further validation with 102 RA patients and 104 HCs. The area under curves (AUC) were calculated after plotting the receiver operating characteristic (ROC) curves. To determine if these miRNAs are specific for RA, the concentrations of these miRNAs were analyzed in 24 patients with osteoarthritis (OA), and 11 patients with systemic lupus erythematosus (SLE). The array analysis and the subsequent confirmation in larger patient cohort identified significant alterations in plasma levels of seven miRNAs. The highest AUC was found for miR-125a-5p, followed in order by miR-24 and miR-26a. Multivariable logistic regression analysis showed that miR-24, miR-30a-5p, and miR-125a-5p were crucial factors for making detection model of RA and provided a formula for Estimated Probability of RA by plasma MiRNA (ePRAM), employing miR-24, miR-30a-5p and miR-125a-5p, which showed increased diagnostic accuracy (AUC: 0.89). The level of miR-24, miR-125a-5p, and ePRAM in OA and SLE patients were lower than that in RA. There was no significant difference in detection for anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA patients. These results suggest that the plasma concentrations of miR-24 and miR-125a-5p, and ePRAM are potential diagnostic markers of RA even if patients were ACPA-negative.
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Affiliation(s)
- Koichi Murata
- Kyoto University Graduate School of Medicine, Department of Orthopaedic Surgery, Sakyo, Kyoto, Japan
| | - Moritoshi Furu
- Kyoto University Graduate School of Medicine, Department of Orthopaedic Surgery, Sakyo, Kyoto, Japan
- Kyoto University Graduate School of Medicine, Department of the Control for Rheumatic Diseases, Sakyo, Kyoto, Japan
| | - Hiroyuki Yoshitomi
- Kyoto University Graduate School of Medicine, Department of Orthopaedic Surgery, Sakyo, Kyoto, Japan
- Kyoto University Graduate School of Medicine, Center for Innovation in Immunoregulative Technology and Therapeutics, Sakyo, Kyoto, Japan
- * E-mail:
| | - Masahiro Ishikawa
- Kyoto University Graduate School of Medicine, Department of Orthopaedic Surgery, Sakyo, Kyoto, Japan
| | - Hideyuki Shibuya
- Kyoto University Graduate School of Medicine, Department of Orthopaedic Surgery, Sakyo, Kyoto, Japan
| | - Motomu Hashimoto
- Kyoto University Graduate School of Medicine, Department of the Control for Rheumatic Diseases, Sakyo, Kyoto, Japan
- Kyoto University Graduate School of Medicine, Department of Rheumatology and Clinical Immunology, Sakyo, Kyoto, Japan
| | - Yoshitaka Imura
- Kyoto University Graduate School of Medicine, Department of Rheumatology and Clinical Immunology, Sakyo, Kyoto, Japan
| | - Takao Fujii
- Kyoto University Graduate School of Medicine, Department of the Control for Rheumatic Diseases, Sakyo, Kyoto, Japan
- Kyoto University Graduate School of Medicine, Department of Rheumatology and Clinical Immunology, Sakyo, Kyoto, Japan
| | - Hiromu Ito
- Kyoto University Graduate School of Medicine, Department of Orthopaedic Surgery, Sakyo, Kyoto, Japan
- Kyoto University Graduate School of Medicine, Department of the Control for Rheumatic Diseases, Sakyo, Kyoto, Japan
| | - Tsuneyo Mimori
- Kyoto University Graduate School of Medicine, Department of the Control for Rheumatic Diseases, Sakyo, Kyoto, Japan
- Kyoto University Graduate School of Medicine, Department of Rheumatology and Clinical Immunology, Sakyo, Kyoto, Japan
| | - Shuichi Matsuda
- Kyoto University Graduate School of Medicine, Department of Orthopaedic Surgery, Sakyo, Kyoto, Japan
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