The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Endocrine Therapy for Triple Negative Breast Cancer:  Targeting the Androgen Receptor - When and How? (#116)

Jennifer Richer 1
  1. University of Colorado, Aurora, CO, United States

Androgen receptor (AR) protein is expressed in up to half of triple negative breast cancers (TNBC) and is often retained or even increased during progression to metastatic disease. AR+ TNBC are slow growing and respond relatively poorly to chemotherapy, yet AR is positively associated with node positive disease. In preclinical models, increased AR facilitates anchorage independent survival and activated AR increased mammosphere formation, tumor initiation, and other stem-cell like properties. Human AR+ TNBC xenografts in mice treated with anti-androgen and chemotherapy do not recur in vivo and AR+ TNBC patient derived xenografts (PDX) show significantly increased growth in response to AR agonist and decreased growth and tumor volume with treatment with antagonist. AR activity under anchorage independent conditions was studied in the presence or absence of AR agonist and antagonists by chromatin immunoprecipitation (ChIP)-seq and RNA-seq. Genes regulated by AR were identified and many confirmed at the protein level. AR chromatin binding and gene regulation increased in TNBC under anchorage independent conditions, and pathway analysis showed enhanced mTOR signaling, aryl hydrocarbon receptor activity, altered metabolism and production of immune-suppressive factors. Nuclear AR and classical AR-regulated genes such as KLK3 and FKBP5 were increased in TNBC PDX in vivo by activation of AR, as were specific tumor-derived immune-suppressive factors. We continue to identify markers of AR dependence and responsiveness to AR-targeted therapy in human TNBC and syngeneic mouse mammary carcinoma models in order to study the effects of endocrine therapy in immune-competent systems.