Targeting the androgen receptor in breast cancer

Estrogen receptor positive (ER+) breast cancer constitutes 70% of all breast cancers and anti-ER therapies such as aromatase inhibitors and tamoxifen represent the main therapeutic strategies in the treatment of this disease. Unfortunately, up to 30% of all primary ER+ tumours will ultimately develop endocrine-resistance and progress on ER-targeted therapies resulting in disease-related morbidity. As a result, there is an urgent medical need for novel therapeutic strategies capable of managing endocrine-resistant breast cancer. Androgen receptor (AR) is expressed in up to 90% of ER+ breast cancers. AR functions as a tumour suppressor in primary ER+ breast cancer and high AR positivity is strongly associated with a favourable patient outcome in the ER+ setting. However, the role of AR in endocrine-resistant breast tumours is highly controversial with data supporting both oncogenic and tumour suppressive functions reported in the literature. Here I have used different modulatory approaches on in vitro and in vivo preclinical models to dissect the functions of AR and determine the best approach to target AR in endocrine-resistant breast cancer. I use an siRNA-mediated approach to knock down AR in cell line models and discover that the basal expression of AR contributes to endocrine-resistance and that loss of AR restores classical ER signalling and reverses endocrine-resistance. However, inhibiting the transcriptional activity of AR with enzalutamide does not recapitulate this effect, suggesting that it is the non-canonical activity of AR which contributes to endocrine-resistance. In contrast, I show that activation of AR by either 5-α dihydrotestosterone (DHT) or selective AR modulator enobosarm in vitro and in patient derived (PDX) models of endocrine-resistance results in significant growth suppression. Mechanistically, this growth-inhibitory effect of AR activation is associated with downregulation of ER signalling. Moreover, I identify AR-regulated genes from the