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Bu W, Li Y. Rat Models of Breast Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1464:123-148. [PMID: 39821024 DOI: 10.1007/978-3-031-70875-6_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
As the first mammal to be domesticated for research purposes, rats served as the primary animal model for various branches of biomedical research, including breast cancer studies, up until the late 1990s and early 2000s. During this time, genetic engineering of mice, but not rats, became routine, and mice gradually supplanted rats as the preferred rodent model. But recent advances in creating genetically engineered rat models, especially with the assistance of CRISPR/Cas9 technology, have rekindled the significance of rats as a critical model in exploring various facets of breast cancer research. This is particularly pronounced in the study of the formation and progression of the estrogen receptor-positive subtype, which remains challenging to model in mice. In this chapter, we embark on a historical journey through the evolution of rat models in biomedical research and provide an overview of the general and histological characteristics of rat mammary glands. Next, we critically review major rat models for breast cancer research, including those induced by carcinogens, hormones, radiation, germline transgenes, germline knockouts, and intraductal injection of retrovirus/lentivirus to deliver oncogenic drivers into mature mammary glands. We also discuss the advances in building rat models using somatic genome editing powered by CRISPR/Cas9. This chapter concludes with our forward-looking perspective on future applications of advanced rat models in critical areas of breast cancer research that have continued to challenge the mouse model community.
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Affiliation(s)
- Wen Bu
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
| | - Yi Li
- Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
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2
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Nicotra R, Lutz C, Messal HA, Jonkers J. Rat Models of Hormone Receptor-Positive Breast Cancer. J Mammary Gland Biol Neoplasia 2024; 29:12. [PMID: 38913216 PMCID: PMC11196369 DOI: 10.1007/s10911-024-09566-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 06/07/2024] [Indexed: 06/25/2024] Open
Abstract
Hormone receptor-positive (HR+) breast cancer (BC) is the most common type of breast cancer among women worldwide, accounting for 70-80% of all invasive cases. Patients with HR+ BC are commonly treated with endocrine therapy, but intrinsic or acquired resistance is a frequent problem, making HR+ BC a focal point of intense research. Despite this, the malignancy still lacks adequate in vitro and in vivo models for the study of its initiation and progression as well as response and resistance to endocrine therapy. No mouse models that fully mimic the human disease are available, however rat mammary tumor models pose a promising alternative to overcome this limitation. Compared to mice, rats are more similar to humans in terms of mammary gland architecture, ductal origin of neoplastic lesions and hormone dependency status. Moreover, rats can develop spontaneous or induced mammary tumors that resemble human HR+ BC. To date, six different types of rat models of HR+ BC have been established. These include the spontaneous, carcinogen-induced, transplantation, hormone-induced, radiation-induced and genetically engineered rat mammary tumor models. Each model has distinct advantages, disadvantages and utility for studying HR+ BC. This review provides a comprehensive overview of all published models to date.
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Affiliation(s)
- Raquel Nicotra
- Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands
- Oncode Institute, Amsterdam, Netherlands
| | - Catrin Lutz
- Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
- Oncode Institute, Amsterdam, Netherlands.
| | - Hendrik A Messal
- Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
- Oncode Institute, Amsterdam, Netherlands.
| | - Jos Jonkers
- Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
- Oncode Institute, Amsterdam, Netherlands.
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3
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Qi WL, Li HY, Wang Y, Xu L, Deng JT, Zhang X, Wang YX, Meng LH. Targeting PI3Kα overcomes resistance to KRas G12C inhibitors mediated by activation of EGFR and/or IGF1R. Acta Pharmacol Sin 2023; 44:1083-1094. [PMID: 36411339 PMCID: PMC10104814 DOI: 10.1038/s41401-022-01015-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 10/18/2022] [Indexed: 11/22/2022]
Abstract
Although several KRasG12C inhibitors have displayed promising efficacy in clinical settings, acquired resistance developed rapidly and circumvented the activity of KRasG12C inhibitors. To explore the mechanism rendering acquired resistance to KRasG12C inhibitors, we established a series of KRASG12C-mutant cells with acquired resistance to AMG510. We found that differential activation of receptor tyrosine kinases (RTKs) especially EGFR or IGF1R rendered resistance to AMG510 in different cellular contexts by maintaining the activation of MAPK and PI3K signaling. Simultaneous inhibition of EGFR and IGF1R restored sensitivity to AMG510 in resistant cells. PI3K integrates signals from multiple RTKs and the level of phosphorylated AKT was revealed to negatively correlate with the anti-proliferative activity of AMG510 in KRASG12C-mutant cells. Concurrently treatment of a novel PI3Kα inhibitor CYH33 with AMG510 exhibited a synergistic effect against parental and resistant KRASG12C-mutant cells in vitro and in vivo, which was accompanied with concomitant inhibition of AKT and MAPK signaling. Taken together, these findings revealed the potential mechanism rendering acquired resistance to KRasG12C inhibitors and provided a mechanistic rationale to combine PI3Kα inhibitors with KRasG12C inhibitors for therapy of KRASG12C-mutant cancers in future clinical trials.
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Affiliation(s)
- Wei-Liang Qi
- Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.501 Haike Road, Shanghai, 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
- College of Pharmacy, Nanchang University, No. 461, Bayi Road, Nanchang, 330006, China
| | - Hui-Yu Li
- Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.501 Haike Road, Shanghai, 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Yi Wang
- Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.501 Haike Road, Shanghai, 201203, China
| | - Lan Xu
- Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.501 Haike Road, Shanghai, 201203, China
| | - Jie-Ting Deng
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xi Zhang
- Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.501 Haike Road, Shanghai, 201203, China
| | - Yu-Xiang Wang
- Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.501 Haike Road, Shanghai, 201203, China.
| | - Ling-Hua Meng
- Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.501 Haike Road, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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4
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Gil Del Alcazar CR, Trinh A, Alečković M, Rojas Jimenez E, Harper NW, Oliphant MU, Xie S, Krop ED, Lulseged B, Murphy KC, Keenan TE, Van Allen EM, Tolaney SM, Freeman GJ, Dillon DA, Muthuswamy SK, Polyak K. Insights into Immune Escape During Tumor Evolution and Response to Immunotherapy Using a Rat Model of Breast Cancer. Cancer Immunol Res 2022; 10:680-697. [PMID: 35446942 PMCID: PMC9177779 DOI: 10.1158/2326-6066.cir-21-0804] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 02/25/2022] [Accepted: 04/20/2022] [Indexed: 11/16/2022]
Abstract
Animal models are critical for the preclinical validation of cancer immunotherapies. Unfortunately, mouse breast cancer models do not faithfully reproduce the molecular subtypes and immune environment of the human disease. In particular, there are no good murine models of estrogen receptor-positive (ER+) breast cancer, the predominant subtype in patients. Here, we show that Nitroso-N-methylurea-induced mammary tumors in outbred Sprague-Dawley rats recapitulate the heterogeneity for mutational profiles, ER expression, and immune evasive mechanisms observed in human breast cancer. We demonstrate the utility of this model for preclinical studies by dissecting mechanisms of response to immunotherapy using combination TGFBR inhibition and PD-L1 blockade. Short-term treatment of early-stage tumors induced durable responses. Gene expression profiling and spatial mapping classified tumors as inflammatory and noninflammatory, and identified IFNγ, T-cell receptor (TCR), and B-cell receptor (BCR) signaling, CD74/MHC II, and epithelium-interacting CD8+ T cells as markers of response, whereas the complement system, M2 macrophage phenotype, and translation in mitochondria were associated with resistance. We found that the expression of CD74 correlated with leukocyte fraction and TCR diversity in human breast cancer. We identified a subset of rat ER+ tumors marked by expression of antigen-processing genes that had an active immune environment and responded to treatment. A gene signature characteristic of these tumors predicted disease-free survival in patients with ER+ Luminal A breast cancer and overall survival in patients with metastatic breast cancer receiving anti-PD-L1 therapy. We demonstrate the usefulness of this preclinical model for immunotherapy and suggest examination to expand immunotherapy to a subset of patients with ER+ disease. See related Spotlight by Roussos Torres, p. 672.
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Affiliation(s)
- Carlos R. Gil Del Alcazar
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Anne Trinh
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Maša Alečković
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Ernesto Rojas Jimenez
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Nicholas W. Harper
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Michael U.J. Oliphant
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Shanshan Xie
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Ethan D. Krop
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Bethlehem Lulseged
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Katherine C. Murphy
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Tanya E. Keenan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- The Broad Institute, Cambridge, Massachusetts
| | - Eliezer M. Van Allen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- The Broad Institute, Cambridge, Massachusetts
| | - Sara M. Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- The Broad Institute, Cambridge, Massachusetts
| | - Gordon J. Freeman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Deborah A. Dillon
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
- Department of Pathology, Harvard Medical School, Boston, Massachusetts
| | - Senthil K. Muthuswamy
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Kornelia Polyak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- The Broad Institute, Cambridge, Massachusetts
- Harvard Stem Cell Institute, Cambridge, Massachusetts
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Miller JL, Bartlett AP, Harman RM, Majhi PD, Jerry DJ, Van de Walle GR. Induced mammary cancer in rat models: pathogenesis, genetics, and relevance to female breast cancer. J Mammary Gland Biol Neoplasia 2022; 27:185-210. [PMID: 35904679 DOI: 10.1007/s10911-022-09522-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 10/16/2022] Open
Abstract
Mammary cancer, or breast cancer in women, is a polygenic disease with a complex etiopathogenesis. While much remains elusive regarding its origin, it is well established that chemical carcinogens and endogenous estrogens contribute significantly to the initiation and progression of this disease. Rats have been useful models to study induced mammary cancer. They develop mammary tumors with comparable histopathology to humans and exhibit differences in resistance or susceptibility to mammary cancer depending on strain. While some rat strains (e.g., Sprague-Dawley) readily form mammary tumors following treatment with the chemical carcinogen, 7,12-dimethylbenz[a]-anthracene (DMBA), other strains (e.g., Copenhagen) are resistant to DMBA-induced mammary carcinogenesis. Genetic linkage in inbred strains has identified strain-specific quantitative trait loci (QTLs) affecting mammary tumors, via mechanisms that act together to promote or attenuate, and include 24 QTLs controlling the outcome of chemical induction, 10 QTLs controlling the outcome of estrogen induction, and 4 QTLs controlling the outcome of irradiation induction. Moreover, and based on shared factors affecting mammary cancer etiopathogenesis between rats and humans, including orthologous risk regions between both species, rats have served as useful models for identifying methods for breast cancer prediction and treatment. These studies in rats, combined with alternative animal models that more closely mimic advanced stages of breast cancer and/or human lifestyles, will further improve our understanding of this complex disease.
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Affiliation(s)
- James L Miller
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, 14853, Ithaca, NY, USA
| | - Arianna P Bartlett
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, 14853, Ithaca, NY, USA
| | - Rebecca M Harman
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, 14853, Ithaca, NY, USA
| | - Prabin Dhangada Majhi
- Department of Veterinary & Animal Sciences, University of Massachusetts, 01003, Amherst, MA, USA
| | - D Joseph Jerry
- Department of Veterinary & Animal Sciences, University of Massachusetts, 01003, Amherst, MA, USA
| | - Gerlinde R Van de Walle
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, 14853, Ithaca, NY, USA.
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Tang D, Kroemer G, Kang R. Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges. Mol Cancer 2021; 20:128. [PMID: 34607583 PMCID: PMC8489073 DOI: 10.1186/s12943-021-01422-7] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 09/08/2021] [Indexed: 02/08/2023] Open
Abstract
Across a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable drug binding sites. Over the past 30 years, this perception has led to the pursuit of indirect routes for targeting RAS expression, processing, upstream regulators, or downstream effectors. After the discovery that the KRAS-G12C variant contains a druggable pocket below the switch-II loop region, it has become possible to design irreversible covalent inhibitors for the variant with improved potency, selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade.
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Affiliation(s)
- Daolin Tang
- The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. .,Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France. .,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France. .,Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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7
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Li HY, Qi WL, Wang YX, Meng LH. Covalent inhibitor targets KRasG12C: A new paradigm for drugging the undruggable and challenges ahead. Genes Dis 2021; 10:403-414. [DOI: 10.1016/j.gendis.2021.08.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/12/2021] [Accepted: 08/27/2021] [Indexed: 12/14/2022] Open
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8
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Gao D, Liu J, Yuan J, Wu J, Kuang X, Kong D, Zheng W, Wang G, Sukumar S, Tu Y, Chen C, Sun S. Intraductal administration of N-methyl-N-nitrosourea as a novel rodent mammary tumor model. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:576. [PMID: 33987274 DOI: 10.21037/atm-21-1540] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background Chemically induced animal models of breast cancer (BC) using N-methyl-N-nitrosourea (MNU) have been widely used in preclinical research. The conventional approach entails intraperitoneal (i.p) or intravenous injection of a carcinogen, leading to tumor induction at unpredictable locations. This study aimed to establish a modified MNU-induced rat mammary tumor model using intraductal (i.duc) administration and to evaluate its biological behavior, morphology, and response to chemotherapy drugs. Methods In a pilot experiment, female Sprague-Dawley (SD) rats were injected with either i.duc MNU or vehicle to test the feasibility of this approach. We explored the appropriate dosage for stable tumor formation in pubescent female SD rats by testing a single i.duc dose of MNU (0.5, 1.0 and 2.0 mg) or vehicle. Results An i.duc injection of 20 µL (1 mg/per duct) MNU in the fourth rat mammary gland induced stable carcinomas in situ. Immunohistochemical (IHC) analysis showed positive expression of estrogen receptor (ER), negative expression of human epidermal growth factor receptor 2 (Her-2), and low expression of Ki-67. Histopathology revealed atypical hyperplasia in the mammary gland 4 weeks after carcinogen injection, developing into carcinoma in situ 5-6 weeks after treatment, with loss of α-SMA and calponin expressions during tumor progression. Albumin-bound paclitaxel (nab-PTX) was injected i.duc and intravenously (i.v) 5 weeks after administration of MNU. The tumor growth rate of the nab-PTX i.duc-treated group was lower than in the i.v and control groups. The number of TUNEL-positive apoptotic cells was significantly higher in the nab-PTX i.duc-treated group. Conclusions Using i.duc MNU (20 µL, 1 mg) to establish a rat mammary tumor model resulted in a predictable location in the rat mammary gland and exhibited better consistency; i.duc administration of nab-PTX permitted a smaller drug dose, but produced a better drug response, than i.v injection.
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Affiliation(s)
- Dongcheng Gao
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jianhua Liu
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jingping Yuan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Juan Wu
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xinwen Kuang
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Deguang Kong
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Weijie Zheng
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Guannan Wang
- Department of Oncology, Georgetown University, Washington, DC, USA
| | - Saraswati Sukumar
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yi Tu
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chuang Chen
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shengrong Sun
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China
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Abstract
One of the mechanisms potentially explaining the discrepancy between the number of human genes and the functional complexity of organisms is generating alternative splice variants, an attribute of the vast majority of multi-exon genes. Members of the RAS family, such as NRAS, KRAS and HRAS, all of which are of significant importance in cancer biology, are no exception. The structural and functional differences of these splice variants, particularly if they contain the canonical (and therefore routinely targeted for diagnostic purposes) hot spot mutations, pose a significant challenge for targeted therapies. We must therefore consider whether these alternative splice variants constitute a minor component as originally thought and how therapies targeting the canonical isoforms affect these alternative splice variants and their overall functions.
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Affiliation(s)
- Erzsébet Rásó
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
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10
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Wang G, Chen C, Pai P, Korangath P, Sun S, Merino VF, Yuan J, Li S, Nie G, Stearns V, Sukumar S. Intraductal fulvestrant for therapy of ERα-positive ductal carcinoma in situ of the breast: a preclinical study. Carcinogenesis 2020; 40:903-913. [PMID: 31046118 DOI: 10.1093/carcin/bgz084] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 04/04/2019] [Accepted: 05/01/2019] [Indexed: 12/18/2022] Open
Abstract
Mammographic screening for breast cancer has led to increased detection of ductal carcinoma in situ (DCIS) and a reappraisal of the necessity of aggressive treatment with their attendant toxicities for a preneoplastic lesion. Fulvestrant, a selective estrogen receptor degrader, is very effective in the treatment of estrogen receptor positive (ER+) breast cancer, but delivery by the painful intramuscular (i.m) route is limiting. We hypothesized that intraductal (i.duc) administration of fulvestrant will provide a direct, safe and effective treatment for DCIS. Mice bearing mammary ductal xenografts of ER+, luciferase-tagged MCF-7 breast cancer cells were administered vehicle or fulvestrant i.m or i.duc. I.duc MCF-7-luc tumors in mice treated with fulvestrant i.duc or i.m grew significantly slower than vehicle control. Whole mount analysis and histopathology showed that i.duc fulvestrant achieved significantly larger cancer-free areas. Western blot analysis showed reduced levels of estrogen receptor alpha (ERα) and its downstream targets, c-Myc and Cyclin D1, and increased levels of ERβ, which is known to inhibit ERα function. Immunohistochemical analysis of tumor sections showed that Ki67 and ERα protein levels decreased by 3-fold, and neoangiogenesis was inhibited by i.duc fulvestrant treatment. I.duc fulvestrant also reduced outgrowth of ERα+, autochthonous N-methyl-N-nitrosourea-induced mammary tumors in rats. Overall, we have shown that i.duc fulvestrant was significantly more effective than, or equivalent in action to i.m fulvestrant in two preclinical models of breast cancer. These studies provide evidence for a novel and safe route for fulvestrant therapy of DCIS and prevention of breast cancer. This preclinical study provides a strong basis for conducting clinical trials for DCIS and early breast cancer.
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Affiliation(s)
- Guannan Wang
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Chuang Chen
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Priya Pai
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Preethi Korangath
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shengrong Sun
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Vanessa F Merino
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jingping Yuan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Suping Li
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.,Chinese Academy of Sciences Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Guangjun Nie
- Chinese Academy of Sciences Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Vered Stearns
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Saraswati Sukumar
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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11
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Mapping Mammary Tumor Traits in the Rat. Methods Mol Biol 2019; 2018:249-267. [PMID: 31228161 DOI: 10.1007/978-1-4939-9581-3_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/03/2023]
Abstract
For nearly a century, the rat has served as a key model for studying the pathophysiology and genetic risk modifiers of breast cancer. Rat mammary tumors that initiate after exposure to carcinogens or estrogens closely resemble the etiological, histopathological, and genomic features of human breast cancer. Recent developments in genome-editing techniques in the rat have also enabled the development of sophisticated models for identifying the genetic modifiers of the nonmalignant tumor microenvironment that contribute to the formation, progression, and outcome of breast cancer. In this protocol review, we discuss the current methodologies for the three genetic mapping techniques in the rat that are widely used for identifying and testing the heritable genetic modifiers of breast cancer.
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12
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Li S, Gestl SA, Gunther EJ. A Multistage Murine Breast Cancer Model Reveals Long-Lived Premalignant Clones Refractory to Parity-Induced Protection. Cancer Prev Res (Phila) 2019; 13:173-184. [PMID: 31699706 DOI: 10.1158/1940-6207.capr-19-0322] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 09/23/2019] [Accepted: 10/29/2019] [Indexed: 11/16/2022]
Abstract
Breast cancers evolve in a multistage process that can span decades after a carcinogenic exposure. It follows that long-lived precursor breast lesions persist in a subclinical state prior to completing malignant transformation, yet widely used breast cancer models lack an experimental framework for targeting premalignant disease. Inspired by classic multistage skin carcinogenesis protocols, we combined chemical carcinogenesis with transgenic mouse modeling to resolve mouse mammary carcinogenesis into discrete initiation and progression stages. At the initiation stage, exposure to the carcinogen 7,12-dimethylbenzanthracene (DMBA) generated "initiated mammary epithelial cells" (iMEC) by introducing a stereotyped HrasQ61L driver mutation. Whether DMBA exposure occurred during puberty or adulthood, mice efficiently acquired iMEC clones that eluded detection by conventional histology, yet were long lived, persisting in a clinically silent state for months in the absence of a cooperating event. At the progression stage, inducible activation of oncogenic Wnt signaling drove rapid and synchronous transformation of latent iMECs into overt mammary carcinomas, while Wnt activation in neighboring normal mammary epithelium yielded only benign hyperplasia over this same time period. Although early parity (completion of a full-term pregnancy) reduces breast cancer risk in some contexts, standard parity-induced protection schemes failed to eliminate iMECs in our multistage model, suggesting Wnt-responsive iMECs are maintained by hormone-independent mechanisms. Variations on our multistage modeling strategy may help to identify and validate cellular and molecular targets for breast cancer chemoprevention.
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Affiliation(s)
- Shuo Li
- The Jake Gittlen Laboratories for Cancer Research, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.,Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Shelley A Gestl
- The Jake Gittlen Laboratories for Cancer Research, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.,Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
| | - Edward J Gunther
- The Jake Gittlen Laboratories for Cancer Research, Pennsylvania State University College of Medicine, Hershey, Pennsylvania. .,Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.,Department of Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
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13
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Moorehead RA. Rodent Models Assessing Mammary Tumor Prevention by Soy or Soy Isoflavones. Genes (Basel) 2019; 10:E566. [PMID: 31357528 PMCID: PMC6722900 DOI: 10.3390/genes10080566] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 06/26/2019] [Accepted: 07/09/2019] [Indexed: 12/14/2022] Open
Abstract
While epidemiological studies performed in Asian countries generally show that high levels of dietary soy are associated with reduced breast cancer risk, studies in Western countries have typically failed to show this correlation. In an attempt to model the preventative actions of soy on mammary tumor development, rodent models have been employed. Thirty-four studies were identified that evaluated the impact of soy products or purified soy isoflavones on mammary tumor initiation (studies evaluating established mammary tumors or mammary tumor cell lines were not included) and these studies were separated into mammary tumors induced by chemical carcinogens or transgenic expression of oncogenes based on the timing of soy administration. Regardless of when soy-based diets or purified isoflavones were administered, no consistent protective effects were observed in either carcinogen-induced or oncogene-induced mammary tumors. While some studies demonstrated that soy or purified isoflavones could reduce mammary tumor incidence, other studies showed either no effect or tumor promoting effects of soy products or isoflavones. Most importantly, only five studies found a decrease in mammary tumor incidence and six studies observed a decrease in tumor multiplicity, two relevant measures of the tumor preventative effects of soy or isoflavones. The variable outcomes of the studies examined were not completely surprising given that few studies employed the same experimental design. Future studies should be carefully designed to more accurately emulate soy consumption observed in Asian cultures including lifetime exposure to less refined soy products and potentially the incorporation of multigenerational feeding studies.
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Affiliation(s)
- Roger A Moorehead
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G2W1, Canada.
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14
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Validation of a low-cost, carbon dioxide-based cryoablation system for percutaneous tumor ablation. PLoS One 2019; 14:e0207107. [PMID: 31269078 PMCID: PMC6608927 DOI: 10.1371/journal.pone.0207107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 06/02/2019] [Indexed: 11/23/2022] Open
Abstract
Breast cancer rates are rising in low- and middle-income countries (LMICs), yet there is a lack of accessible and cost-effective treatment. As a result, the cancer burden and death rates are highest in LMICs. In an effort to meet this need, our work presents the design and feasibility of a low-cost cryoablation system using widely-available carbon dioxide as the only consumable. This system uses an 8-gauge outer-diameter needle and Joule-Thomson expansion to percutaneously necrose tissue with cryoablation. Bench top experiments characterized temperature dynamics in ultrasound gel demonstrated that isotherms greater than 2 cm were formed. Further, this system was applied to mammary tumors in an in vivo rat model and necrosis was verified by histopathology. Finally, freezing capacity under a large heat load was assessed with an in vivo porcine study, where volumes of necrosis greater than 1.5 cm in diameter confirmed by histopathology were induced in a highly perfused liver after two 7-minute freeze cycles. These results demonstrate the feasibility of a carbon-dioxide based cryoablation system for improving solid tumor treatment options in resource-constrained environments.
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15
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Murugan AK, Grieco M, Tsuchida N. RAS mutations in human cancers: Roles in precision medicine. Semin Cancer Biol 2019; 59:23-35. [PMID: 31255772 DOI: 10.1016/j.semcancer.2019.06.007] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 05/13/2019] [Accepted: 06/07/2019] [Indexed: 02/07/2023]
Abstract
Ras proteins play a crucial role as a central component of the cellular networks controlling a variety of signaling pathways that regulate growth, proliferation, survival, differentiation, adhesion, cytoskeletal rearrangements and motility of a cell. Almost, 4 decades passed since Ras research was started and ras genes were originally discovered as retroviral oncogenes. Later on, mutations of the human RAS genes were linked to tumorigenesis. Genetic analyses found that RAS is one of the most deregulated oncogenes in human cancers. In this review, we summarize the pioneering works which allowed the discovery of RAS oncogenes, the finding of frequent mutations of RAS in various human cancers, the role of these mutations in tumorigenesis and mutation-activated signaling networks. We further describe the importance of RAS mutations in personalized or precision medicine particularly in molecular targeted therapy, as well as their use as diagnostic and prognostic markers as therapeutic determinants in human cancers.
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Affiliation(s)
- Avaniyapuram Kannan Murugan
- Department of Molecular Cellular Oncology and Microbiology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549 Japan.
| | - Michele Grieco
- DiSTABiF, Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, via Vivaldi 43, Caserta 81100 Italy
| | - Nobuo Tsuchida
- Department of Molecular Cellular Oncology and Microbiology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549 Japan.
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16
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Abstract
The three RAS genes - HRAS, NRAS and KRAS - are collectively mutated in one-third of human cancers, where they act as prototypic oncogenes. Interestingly, there are rather distinct patterns to RAS mutations; the isoform mutated as well as the position and type of substitution vary between different cancers. As RAS genes are among the earliest, if not the first, genes mutated in a variety of cancers, understanding how these mutation patterns arise could inform on not only how cancer begins but also the factors influencing this event, which has implications for cancer prevention. To this end, we suggest that there is a narrow window or 'sweet spot' by which oncogenic RAS signalling can promote tumour initiation in normal cells. As a consequence, RAS mutation patterns in each normal cell are a product of the specific RAS isoform mutated, as well as the position of the mutation and type of substitution to achieve an ideal level of signalling.
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Affiliation(s)
- Siqi Li
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA
| | - Allan Balmain
- Helen Diller Family Comprehensive Cancer Center and Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA
| | - Christopher M Counter
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
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17
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Escrich E. Mammary Cancer Model Induced by Dimethylbenz(a)Anthracene: A Good Experimental Tool for the Study of Tumour Markers. Int J Biol Markers 2018; 2:109-19. [PMID: 3132515 DOI: 10.1177/172460088700200210] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- E Escrich
- Department de Fisiologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Spain
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18
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Abstract
The presence of mutations activating the N-ras gene was investigated by the polymerase chain reaction technique in twenty patients with acute myeloblastic leukemia (AML) at onset and in four patients with Ph' positive chronic myelogeneous leukemia (CML) either in chronic phase or in blast crisis. Four remission samples and four relapses from the AML cases were also studied. Mutations were found in five out of twenty (25%) untreated AML cases at onset. No mutations were detected in the complete remission samples, two of them with N-ras mutations during the leukemic phase. Two out of the four leukemia relapses were positive for the same N-ras mutation shown at presentation, whereas no new mutations were found in the other two initially negative cases. An N-ras mutation appeared during the blast crisis of one of the four CML, which were all negative during the chronic phase. In conclusion, whereas some data appear to be consistent with a role of the N-ras mutations as initiating events in myeloid leukemias, in other cases N-ras activation seems to represent a factor involved in progression. These data suggest that a partial overlapping between initiation and progression factors could exist in naturally occurring tumors.
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Affiliation(s)
- G Saglio
- Dipartimento di Scienze Biomediche e Università di Torino, Italy
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19
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Tsuchida N, Murugan AK, Grieco M. Kirsten Ras* oncogene: significance of its discovery in human cancer research. Oncotarget 2018; 7:46717-46733. [PMID: 27102293 PMCID: PMC5216832 DOI: 10.18632/oncotarget.8773] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 04/10/2016] [Indexed: 12/24/2022] Open
Abstract
The KRAS/ K-RAS oncogene is crucially involved in human cancer. The term "oncogene" -- i.e., a gene able to transform a normal cell into a tumor cell - was introduced in 1969, but the word was not used in the human carcinogenesis literature until much later. Transforming Kras and Hras oncogenes from the Kirsten and Harvey sarcoma viruses were not identified until the early 1980s due to the complicated structures of the viral genomes. Orthologs of these viral oncogenes were then found in transforming DNA fragments in human cancers in the form of mutated versions of the HRAS and KRAS proto-oncogenes. Thus, RAS genes were the first human oncogenes to be identified. Subsequent studies showed that mutated KRAS acted as an in vivo oncogenic driver, as indicated by studies of anti-EGFR therapy for metastatic colorectal cancers. This review addresses the historical background and experimental studies that led to the discovery of Kirsten Ras as an oncogene, the role of mutated KRAS in human carcinogenesis, and recent therapeutic studies of cancer cells with KRAS mutations.
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Affiliation(s)
- Nobuo Tsuchida
- Graduate School of Medical and Dental Sciences, Tokyo Medical Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
| | | | - Michele Grieco
- DiSTABiF, Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Caserta, Italy
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20
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Gutierrez R, Thompson Y, R. O’Connor T. DNA direct repair pathways in cancer. AIMS MEDICAL SCIENCE 2018. [DOI: 10.3934/medsci.2018.3.284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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21
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Phesse TJ, Durban VM, Sansom OJ. Defining key concepts of intestinal and epithelial cancer biology through the use of mouse models. Carcinogenesis 2017; 38:953-965. [PMID: 28981588 PMCID: PMC5862284 DOI: 10.1093/carcin/bgx080] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 07/12/2017] [Accepted: 08/01/2017] [Indexed: 12/18/2022] Open
Abstract
Over the past 20 years, huge advances have been made in modelling human diseases such as cancer using genetically modified mice. Accurate in vivo models are essential to examine the complex interaction between cancer cells, surrounding stromal cells, tumour-associated inflammatory cells, fibroblast and blood vessels, and to recapitulate all the steps involved in metastasis. Elucidating these interactions in vitro has inherent limitations, and thus animal models are a powerful tool to enable researchers to gain insight into the complex interactions between signalling pathways and different cells types. This review will focus on how advances in in vivo models have shed light on many aspects of cancer biology including the identification of oncogenes, tumour suppressors and stem cells, epigenetics, cell death and context dependent cell signalling.
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Affiliation(s)
- Toby J Phesse
- European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, South Glamorgan, CF24 4HQ, UK
| | - Victoria Marsh Durban
- European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, South Glamorgan, CF24 4HQ, UK
- ReNeuron, Pencoed Business Park, Pencoed, Bridgend, CF35 5HY, UK and
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Garscube Estate, Bearsden, Glasgow, G61 1BD, UK
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22
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Anandi L, Chakravarty V, Ashiq KA, Bodakuntla S, Lahiri M. DNA-dependent protein kinase plays a central role in transformation of breast epithelial cells following alkylation damage. J Cell Sci 2017; 130:3749-3763. [PMID: 28923836 DOI: 10.1242/jcs.203034] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 09/14/2017] [Indexed: 12/25/2022] Open
Abstract
DNA alkylating agents form the first line of cancer chemotherapy. They not only kill cells but also behave as potential carcinogens. MNU, a DNA methylating agent, is well known to induce mammary tumours in rodents. However, the mechanism of tumorigenesis is not well understood. Our study reports a novel role played by DNA-dependent protein kinase (DNA-PK) in methylation damage-induced transformation using three-dimensional breast acinar cultures. Here, we report that exposure of breast epithelial cells to MNU inhibited polarisation at the basolateral domain, increased dispersal of the Golgi at the apical domain and induced an epithelial-to-mesenchymal transition (EMT)-like phenotype as well as invasion. This altered Golgi phenotype correlated with impaired intracellular trafficking. Inhibition of DNA-PK resulted in almost complete reversal of the altered Golgi phenotype and partial rescue of the polarity defect and EMT-like phenotype. The results confirm that methylation damage-induced activation of DNA-PK is a major mechanism in mediating cellular transformation.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Libi Anandi
- Indian Institute of Science Education and Research, Pune, Maharashtra 411008, India
| | - Vaishali Chakravarty
- Indian Institute of Science Education and Research, Pune, Maharashtra 411008, India
| | - K A Ashiq
- Indian Institute of Science Education and Research, Pune, Maharashtra 411008, India
| | - Satish Bodakuntla
- Indian Institute of Science Education and Research, Pune, Maharashtra 411008, India.,Institut Curie, PSL Research University, CNRS UMR3348, F-91405 Orsay, France
| | - Mayurika Lahiri
- Indian Institute of Science Education and Research, Pune, Maharashtra 411008, India
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23
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Showler K, Nishimura M, Daino K, Imaoka T, Nishimura Y, Morioka T, Blyth BJ, Kokubo T, Takabatake M, Fukuda M, Moriyama H, Kakinuma S, Fukushi M, Shimada Y. Analysis of genes involved in the PI3K/Akt pathway in radiation- and MNU-induced rat mammary carcinomas. JOURNAL OF RADIATION RESEARCH 2017; 58:183-194. [PMID: 27738081 PMCID: PMC5571612 DOI: 10.1093/jrr/rrw097] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 07/11/2016] [Accepted: 08/30/2016] [Indexed: 05/31/2023]
Abstract
The PI3K/AKT pathway is one of the most important signaling networks in human breast cancer, and since it was potentially implicated in our preliminary investigations of radiation-induced rat mammary carcinomas, our aim here was to verify its role. We included mammary carcinomas induced by the chemical carcinogen 1-methyl-1-nitrosourea to determine whether any changes were radiation-specific. Most carcinomas from both groups showed activation of the PI3K/AKT pathway, but phosphorylation of AKT1 was often heterogeneous and only present in a minority of carcinoma cells. The negative pathway regulator Inpp4b was significantly downregulated in both groups, compared with in normal mammary tissue, and radiation-induced carcinomas also showed a significant decrease in Pten expression, while the chemically induced carcinomas showed a decrease in Pik3r1 and Pdk1. Significant upregulation of the positive regulators Erbb2 and Pik3ca was observed only in chemically induced carcinomas. However, no genes showed clear correlations with AKT phosphorylation levels, except in individual carcinomas. Only rare carcinomas showed mutations in PI3K/AKT pathway genes, yet these carcinomas did not exhibit stronger AKT phosphorylation. Thus, while AKT phosphorylation is a common feature of rat mammary carcinomas induced by radiation or a canonical chemical carcinogen, the mutation of key genes in the pathways or permanent changes to gene expression of particular signaling proteins do not explain the pathway activation in the advanced cancers. Although AKT signaling likely facilitates cancer development and growth in rat mammary carcinomas, it is unlikely that permanent disruption of the PI3K/AKT pathway genes is a major causal event in radiation carcinogenesis.
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Affiliation(s)
- Kaye Showler
- Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
- Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan
| | - Mayumi Nishimura
- Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan
| | - Kazuhiro Daino
- Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan
| | - Tatsuhiko Imaoka
- Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan
| | - Yukiko Nishimura
- Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan
| | - Takamitsu Morioka
- Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan
| | - Benjamin J. Blyth
- Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan
| | - Toshiaki Kokubo
- Department of Engineering and Safety, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan
| | - Masaru Takabatake
- Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan
| | - Maki Fukuda
- Faculty of Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
| | - Hitomi Moriyama
- Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
- Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan
| | - Shizuko Kakinuma
- Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan
| | - Masahiro Fukushi
- Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
- Faculty of Health Sciences, Tokyo Metropolitan University, Tokyo 116-8551, Japan
| | - Yoshiya Shimada
- Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan
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24
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Alvarado A, Faustino-Rocha AI, Colaço B, Oliveira PA. Experimental mammary carcinogenesis - Rat models. Life Sci 2017; 173:116-134. [PMID: 28188729 DOI: 10.1016/j.lfs.2017.02.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 01/26/2017] [Accepted: 02/06/2017] [Indexed: 12/22/2022]
Abstract
Mammary cancer is one of the most common cancers, victimizing more than half a million of women worldwide every year. Despite all the studies in this field, the current therapeutic approaches are not effective and have several devastating effects for patients. In this way, the need to better understand the mammary cancer biopathology and find effective therapies led to the development of several rodent models over years. With this review, the authors intended to provide the readers with an overview of the rat models used to study mammary carcinogenesis, with a special emphasis on chemically-induced models.
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Affiliation(s)
- Antonieta Alvarado
- Área de Patología, Decanato de Ciencias Veterinarias, Universidad Centroccidental "Lisandro Alvarado", UCLA, Lara, Venezuela; Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
| | - Ana I Faustino-Rocha
- Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, UTAD, Vila Real, Portugal
| | - Bruno Colaço
- Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Department of Zootechnics, School of Agrarian and Veterinary Sciences, UTAD, Vila Real, Portugal
| | - Paula A Oliveira
- Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal; Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, UTAD, Vila Real, Portugal.
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25
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Tu H, Liu Y, Marjanovic M, Chaney EJ, You S, Zhao Y, Boppart SA. Concurrence of extracellular vesicle enrichment and metabolic switch visualized label-free in the tumor microenvironment. SCIENCE ADVANCES 2017; 3:e1600675. [PMID: 28138543 PMCID: PMC5266479 DOI: 10.1126/sciadv.1600675] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 09/19/2016] [Indexed: 05/13/2023]
Abstract
Understanding the role of the tumor microenvironment in carcinogenesis has reshaped cancer research. Events at both microscopic (molecular) and macroscopic (tissue) scales have been identified in engineered tumor microenvironments involving in vitro cultures, live tissue xenografts, and transgenic animals. However, these events have not been comprehensively observed under unperturbed (authentic) conditions free of exogenous labeling or genetic modification. The lack of a suitable imaging methodology has largely limited our understanding of the complex interrelations and possible causal links involved in carcinogenesis and metastasis within the tumor microenvironment. Using multicontrast nonlinear imaging, we visualize endogenous substances in rat and human mammary tumors through their intrinsic nonlinear optical properties, and simultaneously observe angiogenesis, extracellular matrix reorganization, and non-native cell recruitment. We find that all these macroscopic events in the tumor microenvironment require concurrent enrichment of specific extracellular vesicles and a metabolic switch toward biosynthesis. This concurrence at the microscopic scale provides not only new insights into carcinogenesis and metastasis but also a potentially new strategy for cancer diagnosis, surgery, and therapeutics.
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Affiliation(s)
- Haohua Tu
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Yuan Liu
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Marina Marjanovic
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Eric J. Chaney
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Sixian You
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Youbo Zhao
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Stephen A. Boppart
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Department of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
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26
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Basu AK, Pande P, Bose A. Translesion Synthesis of 2'-Deoxyguanosine Lesions by Eukaryotic DNA Polymerases. Chem Res Toxicol 2016; 30:61-72. [PMID: 27760288 PMCID: PMC5241707 DOI: 10.1021/acs.chemrestox.6b00285] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
![]()
With the discovery
of translesion synthesis DNA polymerases, great
strides have been made in the last two decades in understanding the
mode of replication of various DNA lesions in prokaryotes and eukaryotes.
A database search indicated that approximately 2000 articles on this
topic have been published in this period. This includes research involving
genetic and structural studies as well as in vitro experiments using purified DNA polymerases and accessory proteins.
It is a daunting task to comprehend this exciting and rapidly emerging
area of research. Even so, as the majority of DNA damage occurs at
2′-deoxyguanosine residues, this perspective attempts to summarize
a subset of this field, focusing on the most relevant eukaryotic DNA
polymerases responsible for their bypass.
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Affiliation(s)
- Ashis K Basu
- Department of Chemistry, University of Connecticut , Storrs, Connecticut 06269, United States
| | - Paritosh Pande
- Department of Chemistry, University of Connecticut , Storrs, Connecticut 06269, United States
| | - Arindam Bose
- Department of Chemistry, University of Connecticut , Storrs, Connecticut 06269, United States
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27
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Abba MC, Zhong Y, Lee J, Kil H, Lu Y, Takata Y, Simper MS, Gaddis S, Shen J, Aldaz CM. DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations. Oncotarget 2016; 7:64289-64299. [PMID: 27588403 PMCID: PMC5325442 DOI: 10.18632/oncotarget.11733] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 08/12/2016] [Indexed: 11/25/2022] Open
Abstract
Controversy always existed on the utility of chemically induced mouse mammary carcinogenesis models as valid equivalents for the study of human breast cancer. Here, we performed whole exome and RNA sequencing on long latency mammary tumors (218 ± 27 days) induced by the carcinogen 7,12-Dimethylbenzathracene (DMBA) and short latency tumors (65 ± 11 days) induced by the progestin Medroxyprogesterone Acetate (MPA) plus DMBA in CD2F1 mice. Long latency tumors displayed a high frequency of Pi3kca and/or Pten mutations detected in 11 of 13 (85%) long latency cases (14/22, 64% overall). Eighty-two percent (9/11) of tumors carried the Pik3ca H1047L/R hot-spot mutation, as frequently found in human breast cancer. These tumors were luminal-like and mostly ER/PR+, as in humans. Transcriptome profiling indicated a significant activation of the PI3K-Akt pathway (p=3.82e-6). On the other hand MPA+DMBA induced short latency tumors displayed mutations in cancer drivers not commonly found mutated in human breast cancer (e.g. Hras and Apc). These tumors were mostly basal-like and MPA exposure led to Rankl overexpression (60 fold induction) and immunosuppressive gene expression signatures. In summary, long latency DMBA induced mouse mammary tumors reproduce the molecular profile of human luminal breast carcinomas representing an excellent preclinical model for the testing of PIK3CA/Akt/mTOR pathway inhibitory therapies and a good platform for the developing of additional preclinical tools such as syngeneic transplants in immunocompetent hosts.
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MESH Headings
- 9,10-Dimethyl-1,2-benzanthracene
- Animals
- Cell Transformation, Neoplastic/chemically induced
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Class I Phosphatidylinositol 3-Kinases
- DNA Mutational Analysis
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Mammary Neoplasms, Experimental/chemically induced
- Mammary Neoplasms, Experimental/enzymology
- Mammary Neoplasms, Experimental/genetics
- Mammary Neoplasms, Experimental/pathology
- Medroxyprogesterone Acetate
- Mice, Inbred C57BL
- Mice, Inbred DBA
- Mutation
- PTEN Phosphohydrolase/genetics
- Phosphatidylinositol 3-Kinases/genetics
- Proto-Oncogene Proteins c-akt/genetics
- Proto-Oncogene Proteins c-akt/metabolism
- RANK Ligand/genetics
- RANK Ligand/metabolism
- Sequence Analysis, RNA
- Time Factors
- Transcriptome
- Exome Sequencing
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Affiliation(s)
- Martín C. Abba
- CINIBA, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Argentina
- CAETI, Facultad de Tecnología Informática, Universidad Abierta Interamericana (UAI), Argentina
| | - Yi Zhong
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA
| | - Jaeho Lee
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA
| | - Hyunsuk Kil
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA
| | - Yue Lu
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA
| | - Yoko Takata
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA
| | - Melissa S. Simper
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA
| | - Sally Gaddis
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA
| | - Jianjun Shen
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA
| | - C. Marcelo Aldaz
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA
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Li YJ, Liu G, Xia L, Xiao X, Liu JC, Menezes ME, Das SK, Emdad L, Sarkar D, Fisher PB, Archer MC, Zacksenhaus E, Ben-David Y. Suppression of Her2/Neu mammary tumor development in mda-7/IL-24 transgenic mice. Oncotarget 2016; 6:36943-54. [PMID: 26460950 PMCID: PMC4741907 DOI: 10.18632/oncotarget.6046] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 09/23/2015] [Indexed: 12/21/2022] Open
Abstract
Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) encodes a tumor suppressor gene implicated in the growth of various tumor types including breast cancer. We previously demonstrated that recombinant adenovirus-mediated mda-7/IL-24 expression in the mammary glands of carcinogen-treated (methylnitrosourea, MNU) rats suppressed mammary tumor development. Since most MNU-induced tumors in rats contain activating mutations in Ha-ras, which arenot frequently detected in humans, we presently examined the effect of MDA-7/IL-24 on Her2/Neu-induced mammary tumors, in which the RAS pathway is induced. We generated tet-inducible MDA-7/IL-24 transgenic mice and crossed them with Her2/Neu transgenic mice. Triple compound transgenic mice treated with doxycycline exhibited a strong inhibition of tumor development, demonstrating tumor suppressor activity by MDA-7/IL-24 in immune-competent mice. MDA-7/IL-24 induction also inhibited growth of tumors generated following injection of Her2/Neu tumor cells isolated from triple compound transgenic mice that had not been treated with doxycycline, into the mammary fat pads of isogenic FVB mice. Despite initial growth suppression, tumors in triple compound transgenic mice lost mda-7/IL-24 expression and grew, albeit after longer latency, indicating that continuous presence of this cytokine within tumor microenvironment is crucial to sustain tumor inhibitory activity. Mechanistically, MDA-7/IL-24 exerted its tumor suppression effect on HER2+ breast cancer cells, at least in part, through PERP, a member of PMP-22 family with growth arrest and apoptosis-inducing capacity. Overall, our results establish mda-7/IL-24 as a suppressor of mammary tumor development and provide a rationale for using this cytokine in the prevention/treatment of human breast cancer.
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Affiliation(s)
- You-Jun Li
- Department of Anatomy, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin, China
| | - Guodong Liu
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Lei Xia
- Division of Biology, The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, China
| | - Xiao Xiao
- Division of Biology, The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, China
| | - Jeff C Liu
- Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada
| | - Mitchell E Menezes
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Swadesh K Das
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Luni Emdad
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Paul B Fisher
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Michael C Archer
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Eldad Zacksenhaus
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada
| | - Yaacov Ben-David
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,Division of Biology, The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, China
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29
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Tu H, Liu Y, Turchinovich D, Marjanovic M, Lyngsø J, Lægsgaard J, Chaney EJ, Zhao Y, You S, Wilson WL, Xu B, Dantus M, Boppart SA. Stain-free histopathology by programmable supercontinuum pulses. NATURE PHOTONICS 2016; 10:534-540. [PMID: 27668009 PMCID: PMC5031149 DOI: 10.1038/nphoton.2016.94] [Citation(s) in RCA: 134] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 04/18/2016] [Indexed: 05/18/2023]
Abstract
The preparation, staining, visualization, and interpretation of histological images of tissue is well-accepted as the gold standard process for the diagnosis of disease. These methods were developed historically, and are used ubiquitously in pathology, despite being highly time and labor intensive. Here we introduce a unique optical imaging platform and methodology for label-free multimodal multiphoton microscopy that uses a novel photonic crystal fiber source to generate tailored chemical contrast based on programmable supercontinuum pulses. We demonstrate collection of optical signatures of the tumor microenvironment, including evidence of mesoscopic biological organization, tumor cell migration, and (lymph-)angiogenesis collected directly from fresh ex vivo mammary tissue. Acquisition of these optical signatures and other cellular or extracellular features, which are largely absent from histologically processed and stained tissue, combined with an adaptable platform for optical alignment-free programmable-contrast imaging, offers the potential to translate stain-free molecular histopathology into routine clinical use.
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Affiliation(s)
- Haohua Tu
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Correspondence and requests for materials should be addressed to H. T. and S. A. B., ,
| | - Yuan Liu
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Dmitry Turchinovich
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA, Max Planck Institute for Polymer Research, Ackermannweg 10, Mainz, 55128, Germany
| | - Marina Marjanovic
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA, Max Planck Institute for Polymer Research, Ackermannweg 10, Mainz, 55128, Germany
| | - Jens Lyngsø
- NKT Photonics A/S, Blokken 84, 3460 Birkerød, Denmark
| | - Jesper Lægsgaard
- DTU Fotonik, Technical University of Denmark, Ørsteds Plads 343, 2800 Lyngby, Denmark
| | - Eric J. Chaney
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Youbo Zhao
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Sixian You
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA, Max Planck Institute for Polymer Research, Ackermannweg 10, Mainz, 55128, Germany
| | - William L. Wilson
- Department of Materials Science and Engineering, Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Bingwei Xu
- Biophotonic Solutions Inc., East Lansing, Michigan 48823, USA
| | - Marcos Dantus
- Department of Chemistry and Department of Physics, Michigan State University, East Lansing, Michigan 48824, USA
| | - Stephen A. Boppart
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA, Max Planck Institute for Polymer Research, Ackermannweg 10, Mainz, 55128, Germany
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Correspondence and requests for materials should be addressed to H. T. and S. A. B., ,
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30
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Sriwiriyajan S, Tedasen A, Lailerd N, Boonyaphiphat P, Nitiruangjarat A, Deng Y, Graidist P. Anticancer and Cancer Prevention Effects of Piperine-Free Piper nigrum Extract on N-nitrosomethylurea-Induced Mammary Tumorigenesis in Rats. Cancer Prev Res (Phila) 2015; 9:74-82. [DOI: 10.1158/1940-6207.capr-15-0127] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 10/21/2015] [Indexed: 11/16/2022]
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31
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Faustino-Rocha AI, Ferreira R, Oliveira PA, Gama A, Ginja M. N-Methyl-N-nitrosourea as a mammary carcinogenic agent. Tumour Biol 2015; 36:9095-117. [PMID: 26386719 DOI: 10.1007/s13277-015-3973-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 08/21/2015] [Indexed: 02/06/2023] Open
Abstract
The administration of chemical carcinogens is one of the most commonly used methods to induce tumors in several organs in laboratory animals in order to study oncologic diseases of humans. The carcinogen agent N-methyl-N-nitrosourea (MNU) is the oldest member of the nitroso compounds that has the ability to alkylate DNA. MNU is classified as a complete, potent, and direct alkylating compound. Depending on the animals' species and strain, dose, route, and age at the administration, MNU may induce tumors' development in several organs. The aim of this manuscript was to review MNU as a carcinogenic agent, taking into account that this carcinogen agent has been frequently used in experimental protocols to study the carcinogenesis in several tissues, namely breast, ovary, uterus, prostate, liver, spleen, kidney, stomach, small intestine, colon, hematopoietic system, lung, skin, retina, and urinary bladder. In this paper, we also reviewed the experimental conditions to the chemical induction of tumors in different organs with this carcinogen agent, with a special emphasis in the mammary carcinogenesis.
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Affiliation(s)
- Ana I Faustino-Rocha
- Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, University of Trás-os-Montes and Alto Douro, UTAD, 5001-911, Vila Real, Portugal. .,Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), UTAD, 5001-911, Vila Real, Portugal.
| | - Rita Ferreira
- Organic Chemistry of Natural Products and Agrifood (QOPNA), Mass Spectrometry Center, Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal
| | - Paula A Oliveira
- Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, University of Trás-os-Montes and Alto Douro, UTAD, 5001-911, Vila Real, Portugal.,Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), UTAD, 5001-911, Vila Real, Portugal
| | - Adelina Gama
- Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, University of Trás-os-Montes and Alto Douro, UTAD, 5001-911, Vila Real, Portugal.,Animal and Veterinary Research Center (CECAV), School of Agrarian and Veterinary Sciences, UTAD, 5001-911, Vila Real, Portugal
| | - Mário Ginja
- Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences, University of Trás-os-Montes and Alto Douro, UTAD, 5001-911, Vila Real, Portugal.,Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), UTAD, 5001-911, Vila Real, Portugal
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32
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Bloomfield M, McCormack A, Mandrioli D, Fiala C, Aldaz CM, Duesberg P. Karyotypic evolutions of cancer species in rats during the long latent periods after injection of nitrosourea. Mol Cytogenet 2014; 7:71. [PMID: 25614763 PMCID: PMC4302718 DOI: 10.1186/s13039-014-0071-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Accepted: 10/10/2014] [Indexed: 11/22/2022] Open
Abstract
Background A century of research has established that cancers arise from tissues exposed to carcinogens only after long latencies of years to decades and have individual clonal karyotypes. Since speciation from known precursors also depends on long latencies and new species also have individual karyotypes, we and others have recently proposed that carcinogenesis is a form of speciation. According to this theory karyotypic evolutions generate new cancer species from normal cells as follows: Carcinogens induce aneuploidy (Figure 1). By unbalancing thousands of genes aneuploidy automatically destabilizes the karyotype and thus catalyzes random karyotypic variations. Selections of variants with proliferative phenotypes form non-clonal hyperplasias with persistently varying karyotypes. Very rare karyotypic variations form new cancer species with individual clonal karyotypes. Despite destabilization by the resulting congenital aneuploidies, cancer karyotypes are stabilized within narrow margins of variation by clonal selections for cancer-specific autonomy. Because all non-cancerous aneuploidies are unstable, all aneusomies of prospective cancers are joined in single-steps, rather than gradually. Since this mechanism is very inefficient, it predicts long latent periods from carcinogens to cancers and individual clonal cancer karyotypes. Results Here we have tested the predicted roles of karyotypic evolutions during the time course of carcinogenesis in an established experimental system. In this system injection of nitrosourea induces in female rats non-invasive mammary hyperplasias (“tumors”) after two or more months, and invasive carcinomas after six or more months. Accordingly four specific predictions were tested: (1) Invasive cancers are late and carry individual clonal karyotypes and phenotypes, (2) Persistent hyperplasias carry non-clonal karyotypes, (3) Non-clonal hyperplasias generate clonal cancers spontaneously but rarely, (4) Cancer-karyotypes arise with all individual clonal aneusomies in single-steps. All four predictions were experimentally confirmed. Conclusions Our results along with the literature reveal a coherent karyotypic mechanism of carcinogenesis: Carcinogens induce aneuploidy. The inherent instability of aneuploidy automatically catalyzes new karyotypic variations. Aneuploid karyotypes with proliferative phenotypes form varying non-clonal hyperplasias. Rare variations form cancer species with individual clonal karyotypes, which are stabilized by clonal selection for autonomy. The low odds of this mechanism explain the long latencies of carcinogenesis, the individuality and karyotypic clonality of cancers.
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Affiliation(s)
- Mathew Bloomfield
- Department of Molecular and Cell Biology, Donner Laboratory, University of California at Berkeley, Berkeley, CA USA
| | - Amanda McCormack
- Department of Molecular and Cell Biology, Donner Laboratory, University of California at Berkeley, Berkeley, CA USA
| | - Daniele Mandrioli
- Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA
| | - Christian Fiala
- Gynmed Ambulatorium, Mariahilferguertel 37, 1150 Vienna, Austria
| | - C Marcelo Aldaz
- Department of Molecular Carcinogenesis, M. D. Anderson Cancer Center, Smithville, Texas 78957 USA
| | - Peter Duesberg
- Department of Molecular and Cell Biology, Donner Laboratory, University of California at Berkeley, Berkeley, CA USA
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33
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Cox AD, Der CJ. Ras history: The saga continues. Small GTPases 2014; 1:2-27. [PMID: 21686117 DOI: 10.4161/sgtp.1.1.12178] [Citation(s) in RCA: 529] [Impact Index Per Article: 48.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2010] [Revised: 05/17/2010] [Accepted: 05/24/2010] [Indexed: 12/24/2022] Open
Abstract
Although the roots of Ras sprouted from the rich history of retrovirus research, it was the discovery of mutationally activated RAS genes in human cancer in 1982 that stimulated an intensive research effort to understand Ras protein structure, biochemistry and biology. While the ultimate goal has been developing anti-Ras drugs for cancer treatment, discoveries from Ras have laid the foundation for three broad areas of science. First, they focused studies on the origins of cancer to the molecular level, with the subsequent discovery of genes mutated in cancer that now number in the thousands. Second, elucidation of the biochemical mechanisms by which Ras facilitates signal transduction established many of our fundamental concepts of how a normal cell orchestrates responses to extracellular cues. Third, Ras proteins are also founding members of a large superfamily of small GTPases that regulate all key cellular processes and established the versatile role of small GTP-binding proteins in biology. We highlight some of the key findings of the last 28 years.
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Affiliation(s)
- Adrienne D Cox
- Department of Radiation Oncology; Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill; Chapel Hill, NC USA
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34
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Balmain A, Yuspa SH. Milestones in skin carcinogenesis: the biology of multistage carcinogenesis. J Invest Dermatol 2014; 134:E2-7. [PMID: 25302469 DOI: 10.1038/skinbio.2014.2] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Allan Balmain
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA
| | - Stuart H Yuspa
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
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35
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Li YJ, Liu G, Li Y, Vecchiarelli-Federico LM, Liu JC, Zacksenhaus E, Shan SW, Yang BB, Li Q, Dash R, Fisher PB, Archer MC, Ben-David Y. mda-7/IL-24 expression inhibits breast cancer through upregulation of growth arrest-specific gene 3 (gas3) and disruption of β1 integrin function. Mol Cancer Res 2013; 11:593-603. [PMID: 23468528 DOI: 10.1158/1541-7786.mcr-12-0496] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Melanoma differentiation-associated gene (MDA)-7)/interleukin (IL)-24, a member of the IL-10 family of cytokines, inhibits growth of various human cancer cells, yet the underlying mechanism is largely unknown. Here, we report that mda-7/IL-24 efficiently suppresses the development of rat mammary tumors in vivo. Microarray analysis for genes differentially expressed in rat mammary tumor cells overexpressing MDA-7/IL-24 compared with those that do not express this cytokine identified growth arrest-specific gene-3 (gas3) as a target for mda-7/IL-24. Upregulation of gas3 by mda-7/IL-24 was STAT3 dependent. Induction of gas3 inhibited attachment and proliferation of tumor cells in vitro and in vivo by inhibiting the interaction of β1 integrin with fibronectin. A mutated GAS3, which is unable to bind β1 integrin, was also unable to inhibit fibronectin-mediated attachment and cell growth both in adherent and suspension cultures, suggesting that GAS3 exerts its effects through interaction with and regulation of β1 integrin. Thus, mda-7/IL-24 inhibits breast cancer growth, at least in part, through upregulation of GAS3 and disruption of β1 integrin function. Importantly, the expression of the mda-7/IL-24 receptor, IL-20R1, is highly correlated with GAS3 expression in human breast cancer (P = 1.02 × 10(-9)), and the incidence of metastases is significantly reduced in patients with HER2(+) breast cancer expressing high-levels of IL-20R1. Together, our results identify a novel MDA-7/IL-24-GAS3-β1integrin-fibronectin signaling pathway that suppresses breast cancer growth and can be targeted for therapy.
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Affiliation(s)
- You-Jun Li
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
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36
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Stearns V, Mori T, Jacobs LK, Khouri NF, Gabrielson E, Yoshida T, Kominsky SL, Huso DL, Jeter S, Powers P, Tarpinian K, Brown RJ, Lange JR, Rudek MA, Zhang Z, Tsangaris TN, Sukumar S. Preclinical and clinical evaluation of intraductally administered agents in early breast cancer. Sci Transl Med 2012; 3:106ra108. [PMID: 22030751 DOI: 10.1126/scitranslmed.3002368] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Most breast cancers originate in the epithelial cells lining the breast ducts. Intraductal administration of cancer therapeutics would lead to high drug exposure to ductal cells and eliminate preinvasive neoplasms while limiting systemic exposure. We performed preclinical studies in N-methyl-N'-nitrosourea-treated rats to compare the effects of 5-fluorouracil, carboplatin, nanoparticle albumin-bound paclitaxel, and methotrexate to the previously reported efficacy of pegylated liposomal doxorubicin (PLD) on treatment of early and established mammary tumors. Protection from tumor growth was observed with all five agents, with extensive epithelial destruction present only in PLD-treated rats. Concurrently, we initiated a clinical trial to establish the feasibility, safety, and maximum tolerated dose of intraductal PLD. In each eligible woman awaiting mastectomy, we visualized one ductal system and administered dextrose or PLD using a dose-escalation schema (2 to 10 mg). Intraductal administration was successful in 15 of 17 women with no serious adverse events. Our preclinical studies suggest that several agents are candidates for intraductal therapy. Our clinical trial supports the feasibility of intraductal administration of agents in the outpatient setting. If successful, administration of agents directly into the ductal system may allow for "breast-sparing mastectomy" in select women.
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Affiliation(s)
- Vered Stearns
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
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37
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Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Kim MJ, Hayward R, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, Niculescu-Duvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez R, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012; 366:207-15. [PMID: 22256804 PMCID: PMC3724537 DOI: 10.1056/nejmoa1105358] [Citation(s) in RCA: 813] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors. METHODS We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed. RESULTS Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L-mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)-pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L-mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor. CONCLUSIONS Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann-La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.).
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Affiliation(s)
- Fei Su
- Hoffmann-La Roche, Nutley, NJ, USA
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Imaoka T, Nishimura M, Iizuka D, Nishimura Y, Ohmachi Y, Shimada Y. Pre- and postpubertal irradiation induces mammary cancers with distinct expression of hormone receptors, ErbB ligands, and developmental genes in rats. Mol Carcinog 2011; 50:539-52. [PMID: 21374731 DOI: 10.1002/mc.20746] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2010] [Revised: 11/05/2010] [Accepted: 01/14/2011] [Indexed: 11/08/2022]
Abstract
Childhood exposure to carcinogens renders a higher risk of breast cancer. The molecular mechanisms underlying cancer development after such exposure are not, however, well understood. Here we examined how the mechanism of cancer development relates to the age at exposure to ionizing radiation (IR) or the carcinogen 1-methyl-1-nitrosourea (MNU). Pre- and postpubertal (3- and 7-wk-old, respectively) female Sprague-Dawley rats were whole-body γ-irradiated (2 Gy), injected intraperitoneally with MNU (20 mg/kg) or left untreated and were autopsied at 50 wk of age. Mammary carcinomas were examined for estrogen receptor (ER) α, progesterone receptor (PR) and ErbB ligand expression and for expression microarrays. Early histological changes of the ovaries were also evaluated. The incidence of mammary cancer was higher after postpubertal, rather than prepubertal, IR exposure; the inverse was true for MNU. Most cancers were positive for both ERα and PR except for the prepubertal IR group. Cancers of the prepubertal IR group expressed a different set of ErbB ligands from those of the other groups and did not overexpress Areg, which encodes an estrogen-regulated ErbB ligand, or other developmentally related genes including those for hormonally regulated mammary gland development. Prepubertal IR exposure resulted in ovarian dysfunction as revealed by a reduced follicular pool. Evidence thus suggests that mammary carcinogenesis induced by prepubertal IR exposure is independent of ovarian hormones but requires certain ErbB ligands; induction by postpubertal exposure depends on ovarian hormones and different ErbB ligands. In contrast, the mechanism of MNU-induced carcinogenesis was less influenced by the age at exposure.
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Affiliation(s)
- Tatsuhiko Imaoka
- Experimental Radiobiology for Children's Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan
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Hang B. Formation and repair of tobacco carcinogen-derived bulky DNA adducts. J Nucleic Acids 2010; 2010:709521. [PMID: 21234336 PMCID: PMC3017938 DOI: 10.4061/2010/709521] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2010] [Revised: 07/16/2010] [Accepted: 09/17/2010] [Indexed: 01/08/2023] Open
Abstract
DNA adducts play a central role in chemical carcinogenesis. The analysis of formation and repair of smoking-related DNA adducts remains particularly challenging as both smokers and nonsmokers exposed to smoke are repetitively under attack from complex mixtures of carcinogens such as polycyclic aromatic hydrocarbons and N-nitrosamines. The bulky DNA adducts, which usually have complex structure, are particularly important because of their biological relevance. Several known cellular DNA repair pathways have been known to operate in human cells on specific types of bulky DNA adducts, for example, nucleotide excision repair, base excision repair, and direct reversal involving O6-alkylguanine DNA alkyltransferase or AlkB homologs. Understanding the mechanisms of adduct formation and repair processes is critical for the assessment of cancer risk resulting from exposure to cigarette smoke, and ultimately for developing strategies of cancer prevention. This paper highlights the recent progress made in the areas concerning formation and repair of bulky DNA adducts in the context of tobacco carcinogen-associated genotoxic and carcinogenic effects.
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Affiliation(s)
- Bo Hang
- Life Sciences Division, Department of Cancer and DNA Damage Responses, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
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Bergonzini V, Salata C, Calistri A, Parolin C, Palù G. View and review on viral oncology research. Infect Agent Cancer 2010; 5:11. [PMID: 20497566 PMCID: PMC2881002 DOI: 10.1186/1750-9378-5-11] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2009] [Accepted: 05/24/2010] [Indexed: 01/05/2023] Open
Abstract
To date, almost one and a half million cases of cancer are diagnosed every year in the US and nearly 560,000 Americans are expected to die of cancer in the current year, more than 1,500 people a day (data from the American Cancer Society at http://www.cancer.org/). According to the World Health Organization (WHO), roughly 20% of all cancers worldwide results from chronic infections; in particular, up to 15% of human cancers is characterized by a viral aetiology with higher incidence in Developing Countries. The link between viruses and cancer was one of the pivotal discoveries in cancer research during the past Century. Indeed, the infectious nature of specific tumors has important implications in terms of their prevention, diagnosis, and therapy. In the 21st Century, the research on viral oncology field continues to be vigorous, with new significant and original studies on viral oncogenesis and translational research from basic virology to treatment of cancer. This review will cover different viral oncology aspects, starting from the history of viral oncology and moving to the peculiar features of oncogenic RNA and DNA viruses, with a special focus on human pathogens.
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Affiliation(s)
- Valeria Bergonzini
- Department of Histology, Microbiology and Medical Biotechnologies, Division of Microbiology and Virology, University of Padova, Via A Gabelli 63, Padova 35121, Italy
| | - Cristiano Salata
- Department of Histology, Microbiology and Medical Biotechnologies, Division of Microbiology and Virology, University of Padova, Via A Gabelli 63, Padova 35121, Italy
| | - Arianna Calistri
- Department of Histology, Microbiology and Medical Biotechnologies, Division of Microbiology and Virology, University of Padova, Via A Gabelli 63, Padova 35121, Italy
| | - Cristina Parolin
- Department of Biology, University of Padova, Via Ugo Bassi 58B, Padova 35123, Italy
| | - Giorgio Palù
- Department of Histology, Microbiology and Medical Biotechnologies, Division of Microbiology and Virology, University of Padova, Via A Gabelli 63, Padova 35121, Italy
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N-nitroso-N-methylurea and N-nitroso-N-ethylurea induce upregulation of cellular NF-κ B activity through protein kinase C-dependent pathway in human malignant keratinocytes. Arch Pharm Res 2010; 33:133-9. [DOI: 10.1007/s12272-010-2235-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2009] [Revised: 07/31/2009] [Accepted: 10/14/2009] [Indexed: 11/30/2022]
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Ehrlich D, Bruder E, Thome MA, Gutt CN, von Knebel Doeberitz M, Niggli F, Perantoni AO, Koesters R. Nuclear accumulation of beta-catenin protein indicates activation of wnt signaling in chemically induced rat nephroblastomas. Pediatr Dev Pathol 2010; 13:1-8. [PMID: 19348510 PMCID: PMC2990985 DOI: 10.2350/08-03-0443.1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Aberrant wnt signaling caused by mutations in CTNNB1 occurs in about 15% of Wilms tumors, and these mutations appear to be dependent on the concomitant mutational inactivation of the zinc-finger protein WT1. Nuclear beta-catenin protein, a substitute marker of active wnt signaling, has been detected in an even higher proportion (>50%) of Wilms tumors, suggesting alternative genetic pathways leading to beta-catenin activation. Thus, targeting wnt signaling may become an important future therapeutic strategy in Wilms tumor patients. Currently, chemically induced rat nephroblastomas provide the only available rodent model for this tumor. To determine the contribution of active wnt signaling in this model, we investigated 24 chemically induced rat nephroblastomas for beta-catenin protein expression and for Ctnnb1 and WT1 mutations. Immunohistochemistry showed focal strong nuclear accumulation of beta-catenin protein in 18 of 24 tumors, although in a heterogenous pattern. Blastemal and mesenchymal compartments displayed nuclear-positive cells more frequently than areas of epithelial differentiation. Interestingly, we found no mutation of exon 3 of Ctnnb1 and no mutation within the zinc-finger region of WT1 in any of the 24 tumors analyzed. In conclusion, our findings suggest activation of wnt signaling in the majority (63%) of chemically induced rat nephroblastomas. Nuclear expression of beta-catenin in the absence of Ctnnb1 mutations implies, however, alternate mutational targets in rat nephroblastomas.
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Affiliation(s)
- D Ehrlich
- Division of Applied Tumor Biology, Institute of Pathology, University Hospital of Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany
| | - E Bruder
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - MA Thome
- Department of General, Abdominal and Transplant Surgery, University Hospital of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - CN Gutt
- Department of General, Abdominal and Transplant Surgery, University Hospital of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - M von Knebel Doeberitz
- Division of Applied Tumor Biology, Institute of Pathology, University Hospital of Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany
| | - F Niggli
- Children’s Hospital of Zurich, Zurich, Switzerland
| | - AO Perantoni
- Labaratory of Comparative Carcinogenesis, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - R Koesters
- Division of Applied Tumor Biology, Institute of Pathology, University Hospital of Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany
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Imaoka T, Nishimura M, Iizuka D, Daino K, Takabatake T, Okamoto M, Kakinuma S, Shimada Y. Radiation-induced mammary carcinogenesis in rodent models: what's different from chemical carcinogenesis? JOURNAL OF RADIATION RESEARCH 2009; 50:281-293. [PMID: 19506345 DOI: 10.1269/jrr.09027] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Ionizing radiation is one of a few well-characterized etiologic factors of human breast cancer. Laboratory rodents serve as useful experimental models for investigating dose responses and mechanisms of cancer development. Using these models, a lot of information has been accumulated about mammary gland cancer, which can be induced by both chemical carcinogens and radiation. In this review, we first list some experimental rodent models of breast cancer induction. We then focus on several topics that are important in understanding the mechanisms and risk modification of breast cancer development, and compare radiation and chemical carcinogenesis models. We will focus on the pathology and natural history of cancer development in these models, genetic changes observed in induced cancers, indirect effects of carcinogens, and finally risk modification by reproductive factors and age at exposure to the carcinogens. In addition, we summarize the knowledge available on mammary stem/progenitor cells as a potential target of carcinogens. Comparison of chemical and radiation carcinogenesis models on these topics indicates certain similarities, but it also indicates clear differences in several important aspects, such as genetic alterations of induced cancers and modification of susceptibility by age and reproductive factors. Identification of the target cell type and relevant translational research for human risk management may be among the important issues that are addressed by radiation carcinogenesis models.JRRS Incentive Award in 2009.
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Affiliation(s)
- Tatsuhiko Imaoka
- Experimental Radiobiology for Children's Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, Japan.
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Needleman SW. RasProtooncogene Activation in Acute Myeloid Leukemia and Related Disorders. Leuk Lymphoma 2009; 5:85-91. [DOI: 10.3109/10428199109068110] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Abstract
The purpose of this review is to summarize the evidence that can be used to reconstruct the etiology of human cancers from mutations found in tumors. Mutational spectra of the tumor suppressor gene p53 (TP53) are tumor specific. In several cases, these mutational spectra can be linked to exogenous carcinogens, most notably for sunlight-associated skin cancers, tobacco-associated lung cancers, and aristolochic acid-related urothelial tumors. In the TP53 gene, methylated CpG dinucleotides are sequences selectively targeted by endogenous and exogenous mutagenic processes. Recent high-throughput sequencing efforts analyzing a large number of genes in cancer genomes have so far, for the most part, produced mutational spectra similar to those in TP53 but have unveiled a previously unrecognized common G to C transversion mutation signature at GpA dinucleotides in breast cancers and several other cancers. Unraveling the origin of these G to C mutations will be of importance for understanding cancer etiology.
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Samuelson E, Nilsson J, Walentinsson A, Szpirer C, Behboudi A. Absence of Ras mutations in rat DMBA-induced mammary tumors. Mol Carcinog 2009; 48:150-5. [PMID: 18649354 DOI: 10.1002/mc.20464] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Animal cancer models reduce genetic background heterogeneity and thus, may facilitate identification and analysis of specific genetic aberrations in tumor cells. Rat and human mammary glands have high similarity in physiology and show comparable hormone responsiveness. Thus, spontaneous and carcinogen (e.g., NMU and DMBA)-induced rat mammary models are valuable tools for genetic studies of breast cancer. In NMU-induced rat mammary tumors, activating mutations in Hras codon 12 have frequently been reported and are supposed to contribute to the mammary carcinogenic process. Involvement of Ras mutations in DMBA-induced tumors is less clear. In the present study we investigated the mutation status of the three Ras genes, Hras, Kras, and Nras, in DMBA-induced rat mammary tumors. We examined codons 12, 13, and 61 of all three genes for mutations in 71 tumors using direct sequencing method that in experimental conditions is sensitive enough to detect single nucleotide mutations even when present in only 25% of the test sample. No activating Ras gene mutation was found. Thus, in contrast to NMU-induced rat mammary tumor, tumorigenesis in DMBA-induced rat mammary tumors seems to be independent on activating mutations in the Ras genes. Our finding suggests that the genetic pathways selected in mammary tumor development are influenced by and perhaps dependent on the identity of the inducing agent, again emphasizing the importance of tumor etiology on the genetic changes in the tumor cells.
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Affiliation(s)
- Emma Samuelson
- Genetics, Cell and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
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Abstract
In the century since its inception, the field of tumor virology has provided groundbreaking insights into the causes of human cancer. Peyton Rous founded this scientific field in 1911 by discovering an avian virus that induced tumors in chickens; however, it took 40 years for the scientific community to comprehend the effect of this seminal finding. Later identification of mammalian tumor viruses in the 1930s by Richard Shope and John Bittner, and in the 1950s by Ludwik Gross, sparked the first intense interest in tumor virology by suggesting the possibility of a similar causal role for viruses in human cancers. This change in attitude opened the door in the 1960s and 1970s for the discovery of the first human tumor viruses--EBV, hepatitis B virus, and the papillomaviruses. Such knowledge proved instrumental to the development of the first cancer vaccines against cancers having an infectious etiology. Tumor virologists additionally recognized that viruses could serve as powerful discovery tools, leading to revolutionary breakthroughs in the 1970s and 1980s that included the concept of the oncogene, the identification of the p53 tumor suppressor, and the function of the retinoblastoma tumor suppressor. The subsequent availability of more advanced molecular technologies paved the way in the 1980s and 1990s for the identification of additional human tumor viruses--human T-cell leukemia virus type 1, hepatitis C virus, and Kaposi's sarcoma virus. In fact, current estimates suggest that viruses are involved in 15% to 20% of human cancers worldwide. Thus, viruses not only have been shown to represent etiologic agents for many human cancers but have also served as tools to reveal mechanisms that are involved in all human malignancies. This rich history promises that tumor virology will continue to contribute to our understanding of cancer and to the development of new therapeutic and preventive measures for this disease in the 21st century.
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Affiliation(s)
- Ronald T Javier
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA.
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Affiliation(s)
- Lawrence A. Loeb
- Department of Pathology, The Gottstein Memorial Cancer Research Laboratory, University of Washington, Seattle, Washington
| | - Curtis C. Harris
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH Bethesda, Maryland
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Abstract
Extensive research on the Ras proteins and their functions in cell physiology over the past 30 years has led to numerous insights that have revealed the involvement of Ras not only in tumorigenesis but also in many developmental disorders. Despite great strides in our understanding of the molecular and cellular mechanisms of action of the Ras proteins, the expanding roster of their downstream effectors and the complexity of the signalling cascades that they regulate indicate that much remains to be learnt.
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Affiliation(s)
- Antoine E. Karnoub
- Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
| | - Robert A. Weinberg
- Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
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Ekanayake KS, Lebreton PR. Model transition states for methane diazonium ion methylation of guanine runs in oligomeric DNA. J Comput Chem 2007; 28:2352-65. [PMID: 17476668 DOI: 10.1002/jcc.20754] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The DNA reaction pattern of the methane diazonium ion, which is the reactive intermediate formed from several carcinogenic methylating agents, was examined at N7 and O(6) sites in guanine runs occurring in oligonucleotides and model oligonucleotides. Density functional B3LYP/6-31G*, and SCF 3-21G and STO-3G energies of model transition states were calculated in the gas phase and in the CPCM reaction field. For nucleotides containing two, three, and four stacked guanines with counterions in the gas phase, O(6) reactivity is greater than N7 reactivity. In the reaction field, N7 reactivity is 9.0 to 9.8 times greater than O(6) reactivity. For a double-stranded oligonucleotide containing two stacked guanines with counterions in the reaction field, the N7 and O(6) reactivities of the 3'-guanine are 3.9 times greater than the corresponding sites in the 5'-guanine. For double-stranded oligonucleotides with three or four stacked guanines and counterions, the reactivities of the interior guanines are higher than corresponding reactivities of guanines at the ends. These reaction patterns agree with most of the available experimental data. Activation energy decomposition analysis for gas-phase reactions in a double-stranded dinucleotide containing two stacked guanines with counterions indicates that selectivity at O(6) is almost entirely due to electrostatic forces. Selectivity at N7 also has a large electrostatic interaction. However, the orbital interaction also contributes significantly to the gas-phase selectivity, accounting for 32% of the total interaction energy difference between the 3'- and 5'-guanine reactions. In aqueous solution, the relative orbital contribution to N7 selectivity is likely to be larger.
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