Targeting Androgen Receptor in Estrogen Receptor-Negative Breast Cancer

Abstract

Summary Endocrine therapies for breast cancer that target the estrogen receptor (ER) are ineffective in the 25-30% of cases that are ER negative (ER−). Androgen receptor (AR) is expressed in 60-70% of breast tumors, independent of ER status. How androgens and AR regulate breast cancer growth remains largely unknown. We find that AR is enriched in ER−breast tumors that over-express HER2. Through analysis of the AR cistrome and androgen-regulated gene expression in ER−/HER2+ breast cancers we find that AR mediates ligand-dependent activation of Wnt and HER2 signaling pathways through direct transcriptional induction of WNT7B and HER3. Specific targeting of AR, Wnt or HER2 signaling impairs androgen-stimulated tumor cell growth suggesting potential therapeutic approaches for ER−/HER2+ breast cancers.

An androgen receptor mutation in the MDA-MB-453 cell line model of molecular apocrine breast cancer compromises receptor activity

“…We and others have previously shown that MDA-MB-453 cells express very high levels of AR compared with other breast cancer cell lines, with the levels being comparable to those seen in the LNCaP prostate cancer cell line (Hall et al 1994, Birrell et al 1995, Lehmann et al 2011, Robinson et al 2011. Moreover, like prostate cancer cells, but in contrast to most AR(C), ER(C) breast cancer cell lines, proliferation of MDA-MB-453 cells is stimulated by androgens in an AR-dependent manner (Birrell et al 1995, Doane et al 2006, Naderi & Hughes-Davies 2008, Ni et al 2011. Recent studies have shown that AR signaling in MDA-MB-453 cells stimulates a forkhead box A1 (FOXA1)-dependent transcriptional program that is similar to that associated with estrogen signaling in ER(C) luminal breast cancers or cell line models of luminal disease (Doane et al 2006, Robinson et al 2011.…”

“…Recent studies have shown that AR signaling in MDA-MB-453 cells stimulates a forkhead box A1 (FOXA1)-dependent transcriptional program that is similar to that associated with estrogen signaling in ER(C) luminal breast cancers or cell line models of luminal disease (Doane et al 2006, Robinson et al 2011. Furthermore, AR signaling induces Wnt/b-catenin signaling in a manner that subsequently augments the Erbb2 pathway to promote proliferation in MDA-MB-453 cells (Ni et al 2011). These findings support the development of therapeutic strategies for ER(K) breast cancer that target the AR, particularly for tumors that possess a steroid receptor profile characteristic of apocrine breast cancer, i.e.…”

“…5a-dihydrotestosterone, DHT) and synthetic (e.g. methyltrienolone, R1881) non-aromatizable androgens, it is inhibited by the synthetic progestin medroxyprogesterone acetate (MPA; Birrell et al 1995, Bentel et al 1999, Doane et al 2006, Naderi & Hughes-Davies 2008, Ni et al 2011. These proliferative responses are attenuated by co-treatment with an AR antagonist, suggesting that they are mediated by the AR (Birrell et al 1995, Bentel et al 1999.…”

Influence of stromal–epithelial interactions on androgen action

“…Ni et al (2011) showed that AR transcriptionally activates the Wnt and Her2 pathways in a ligand-dependent manner. This indicates a possible role for AR therapeutic targeting in Her2-positive breast cancer.…”

Krüppel-like factor 5 in human breast carcinoma: a potent prognostic factor induced by androgens

“…Especially, functional cross talk between AR and HER2 signaling has been proposed in ER-negative/HER2-positive breast carcinomas (Naderi & Hughes-Davies 2008, Ni et al 2011. Naderi & Hughes-Davies (2008) demonstrated that growth stimulatory effect of heregulin, a ligand of HER1 and HER3, was inhibited by AR inhibitor flutamide in MDA-MB-453 cells.…”