Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Steroid receptor cross talk in breast cancer: molecular insights and therapeutic implications (#264)

Wayne Tilley 1

The estrogen receptor-α (ER), androgen receptor (AR) and progesterone receptor (PR) 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. The action and interaction between these receptors underpins reproductive organ development and maturation in men and women. Accordingly, they also have important roles in diseases of these tissues, including breast and prostate cancer in which ER and AR, respectively, are key drivers and therapeutic targets. My laboratory has been investigating steroid receptor action in breast and prostate cancer for over 30 years. In the breast cancer space, we have been exploring crosstalk between ER and AR, or more recently PR, to explain disease heterogeneity, response to target therapies, and disease outcomes, with view to forging new possibilities for therapeutic targeting. All three receptors have historically been targeted in the treatment of breast cancer, so a wide range of old and new generation drugs are available, offering the opportunity for drug repurposing and a faster track to clinical translation compared to new drugs that have never been tested in people. In the prostate cancer space, we have been focussing on how to better target the AR, which remains the key driver of disease at all stages of progression. On the horizon are new targeting strategies aimed to outsmart known adaptive mechanisms, particularly in terms of targeting regions of the receptor that lie outside of the ligand binding domain. While these new strategies hold great promise for more effective AR inhibition, historical experience of employing androgen deprivation therapy raises a key question: will more effective AR silencing lead to more durable disease regression and significantly extend life for men with metastatic prostate cancer or will it reveal yet unknown treatment-induced adaptations that allow the disease to persist? A similar problem exists in the field of ER-positive breast cancer, in which more effective inhibition of ER has led to more aggressive forms of treatment resistant disease. There is much to be learned from studying these hormone-driven cancers in parallel, with discoveries in one field informing the other.