The Estrogen, Progesterone and Androgen Receptors (ER, PR and AR) are critical components of steroid hormone signaling that act as transcription factors to regulate gene expression, playing important roles in breast development and breast tumourigenesis, where ≈70% of breast cancers (BC) express ER and/or PR, or AR. Understanding the relation between normal epithelial cell types and the different subtypes of breast cancer are fundamental to gaining insight into cell types predisposed to tumourigenesis (1).
50% of HER2 positive breast cancers express AR. While HER2-directed therapies are effective and have improved the survival outcomes in patients with this subset of early stage breast cancer, there is still a significant proportion who develop resistance to this treatment and eventually succumb to the disease. More effective therapies are therefore still required.
Antiandrogen therapies are not currently used to treat breast cancer, but there is emerging preclinical data on its role in tumourigenesis. The group demonstrated that AR mediates ligand-dependent activation of Wnt and HER2 signaling pathways through direct transcriptional induction of WNT7B and HER3 (2). Specific targeting of AR, Wnt or HER2 signaling impairs androgen-stimulated tumour cell growth in vitro, suggesting a novel therapeutic approach for ER-HER2+ breast cancers. The group subsequently found that direct AR regulation of MYC cooperates with AR-mediated activation of HER2/HER3 signaling, demonstrating a novel regulatory network in molecular apocrine breast cancers regulated by androgens and AR in which MYC plays a central role both as a key target and as a cooperating transcription factor to drive oncogenic growth (3). These data provide strong preclinical rationale for targeting AR in ER-HER2+ BCs. We therefore hypothesise that combination therapy with HER2 and AR targeted therapy would lead to more effective tumour targeting of this BC subtype.