Oral Presentation Joint 2016 COSA and ANZBCTG Annual Scientific Meeting

Targeting progesterone and androgen receptors to enhance ER-target therapies in breast cancer (#108)

Wayne Tilley 1
  1. University of Adelaide, Adelaide, SA, Australia

Therapies that modulate estrogen receptor-α (ER) action have improved the survival of patients with ER-positive breast cancer, but resistance to treatment is a major clinical problem. Therefore the targeting of alternative/parallel signalling pathways is required to improve the efficacy and benefit of currently available treatments. Emerging data have shown that other sex hormone receptors may regulate the sites at which ER binds to DNA to suppress the oncogenic activity of ER in breast cancer. The ER, progesterone receptor (PR) and androgen receptor (AR) are ligand-activated transcription factors that bind DNA and interact with a host of other nuclear proteins to regulate gene expression. The cognate hormones and their receptors are structurally and functionally related. Progesterone is a precursor hormone for androgen, which is converted to estrogen; ERα is the prototype from which AR and then PR evolved. Our recent findings indicate that cross-talk between PR or AR with ER in breast cancer can influence response to ER-target therapies and disease outcomes. We recently showed that the PR can reprogram the ER DNA binding landscape towards genes associated with a favourable outcome. Similarly, the AR, which is expressed in the majority of breast cancers, can reprogram ER DNA binding to inhibit the growth of ER-positive tumours.  All three receptors have historically been targeted in the treatment of breast cancer, with a wide range of old and new generation drugs available, offering the opportunity for drug re-purposing and a faster track to clinical translation compared to new drugs that require extensive clinical evaluation. Despite the potential benefit of targeting PR or AR in ER-positive breast cancer, uncertainties remain. For example, there is debate on what PR or AR ligands would be most beneficial in treating women with ER-positive disease. Moreover, AR antagonists as well as selective androgen receptor modulators (SARMs) that activate AR in breast cancer cells are currently being evaluated as potential therapeutic strategies. These issues highlight ongoing uncertainty regarding the best approach to target PR or AR in ER-positive disease. It is therefore critical that the mechanisms of crosstalk between ER and PR or AR be fully elucidated and the effect on reprogramming of ER tested in optimal preclinical models to better inform the design of clinical trials. Additionally, biomarkers of response to PR and AR target therapies need to be established to facilitate introduction of these adjunct ER target therapies into clinical practice.