MMTV-PyMT and Derived Met-1 Mouse Mammary Tumor Cells as Models for Studying the Role of the Androgen Receptor in Triple-Negative Breast Cancer Progression
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Triple-negative breast cancer (TNBC) has a faster rate of metastasis compared to other breast cancer subtypes, and no effective targeted therapies are currently FDA-approved. Recent data indicate that the androgen receptor (AR) promotes tumor survival and may serve as a potential therapeutic target in TNBC. Studies of AR in disease progression and the systemic effects of anti-androgens have been hindered by the lack of an AR-positive (AR+) immunocompetent preclinical model. In this study, we identified the transgenic MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mouse mammary gland carcinoma model of breast cancer and Met-1 cells derived from this model as tools to study the role of AR in breast cancer progression. AR protein expression was examined in late-stage primary tumors and lung metastases from MMTV-PyMT mice as well as in Met-1 cells by immunohistochemistry (IHC). Sensitivity of Met-1 cells to the AR agonist dihydrotestosterone (DHT) and anti-androgen therapy was examined using cell viability, migration/invasion, and anchorage-independent growth assays. Late-stage primary tumors and lung metastases from MMTV-PyMT mice and Met-1 cells expressed abundant nuclear AR protein, while negative for estrogen and progesterone receptors. Met-1 sensitivity to DHT and AR antagonists demonstrated a reliance on AR for survival, and AR antagonists inhibited invasion and anchorage-independent growth. These data suggest that the MMTV-PyMT model and Met-1 cells may serve as valuable tools for mechanistic studies of the role of AR in disease progression and how anti-androgens affect the tumor microenvironment.
KeywordsBreast Cancer Androgen Receptor Enzalutamide Androgen Receptor Expression TNBC Cell
The authors thank Susan Kane from the City of Hope for providing MMTV-PyMT tissue; Alexander Borowsky from the University of California – Davis for permission to use the Met-1 cell line, the University of Colorado Denver Tissue Biobanking and Processing Core and the University of Colorado Cancer Center Tissue Culture Core, both supported by the National Institute of Health/National Cancer Institute Cancer Core Support Grant P30 CA046934, for experimental assistance; and Britta Jacobsen for critical reading of the manuscript. Enzalutamide was provided by Astellas, Inc. and Medivation, Inc. (Medivation, Inc. was acquired by Pfizer, Inc. in September 2016).
Compliance with Ethical Standards
This study was funded by a National Institute of Health R01 CA187733-01A1 to JKR; NIH NRSA T32 CA190216-01A1 postdoctoral fellowship to JLC; US Army Synergistic Idea Development Awards W81XWH-10-1-0179 and W81XWH-15-1 to JAK, JSJ, JAP, JN, and DPMcD; Breast Cancer Research Foundation grant to BSK; and enzalutamide was provided by Astellas, Inc. and Medivation, Inc. (Medivation, Inc. was acquired by Pfizer, Inc. in September 2016).
Conflict of Interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
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