TY - JOUR
T1 - 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
AU - Christenson, Jessica L.
AU - Butterfield, Kiel T.
AU - Spoelstra, Nicole S.
AU - Norris, John D.
AU - Josan, Jatinder S.
AU - Pollock, Julie A.
AU - McDonnell, Donald P.
AU - Katzenellenbogen, Benita S.
AU - Katzenellenbogen, John A.
AU - Richer, Jennifer K.
N1 - Funding Information:
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).
Funding Information:
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).
Publisher Copyright:
© 2017, Springer Science+Business Media New York.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
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U2 - 10.1007/s12672-017-0285-6
DO - 10.1007/s12672-017-0285-6
M3 - Article
C2 - 28194662
AN - SCOPUS:85012295463
VL - 8
SP - 69
EP - 77
JO - Hormones and Cancer
JF - Hormones and Cancer
SN - 1868-8497
IS - 2
ER -