Targeting Androgen Receptor in Estrogen Receptor-Negative Breast Cancer

SummaryEndocrine 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 overexpress 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.

► AR is highly expressed in ER–/HER2+ breast tumors
► Androgen and AR stimulate the growth of ER–/HER2+ breast cancer cells
► AR activates Wnt and HER2 pathways by transcriptional induction of WNT7B and HER3
► Targeting AR effectively inhibits the growth of ER–/HER2+ breast tumors