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

Horm Cancer. 2017 Apr;8(2):69-77. doi: 10.1007/s12672-017-0285-6. Epub 2017 Feb 13.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Antagonists / administration & dosage
  • Androgen Antagonists / pharmacology
  • Animals
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Dihydrotestosterone / administration & dosage
  • Dihydrotestosterone / pharmacology
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / secondary
  • Mammary Neoplasms, Experimental / metabolism*
  • Mammary Tumor Virus, Mouse / physiology
  • Mice
  • Mice, Transgenic
  • Receptors, Androgen / metabolism*
  • Triple Negative Breast Neoplasms / metabolism*

Substances

  • AR protein, human
  • AR protein, mouse
  • Androgen Antagonists
  • Receptors, Androgen
  • Dihydrotestosterone