Investigating the Role of Androgen Receptor Signalling in Oestrogen Receptor Positive Breast Cancer

Breast cancer (BrCa) is the most common cancer in the UK. The majority of BrCa cases are oestrogen receptor α (ERα) positive, and sensitive to endocrine therapies (antioestrogens and aromatase inhibitors). Endocrine therapies for ERα-positive disease are effective initially, but often fail and the disease progresses to the endocrine resistant stage, for which few therapeutic options exist. The androgen receptor (AR) is the most commonly expressed steroid receptor in BrCa, occurring in up to 90% of cases. AR expression in early disease is associated with positive prognostic outcomes in ERα-positive disease. However, AR expression has also been associated with endocrine resistance. These different roles of AR could be because of the changes in the crosstalk between AR and ERα at different stages of the disease, and these changes might have important implications in endocrine resistance. Hence, this study aimed to understand the role of AR in ERα-positive disease and how this crosstalk is affected by antioestrogen treatments. Crosstalk studies between the two steroid receptors in ERα-positive cell lines (MCF7, T47D) demonstrated that AR-ERα crosstalk is inhibitory, and that antioestrogens can reverse the inhibitory effect of ERα upon AR target gene expression. This increase in AR activity appears to be as a result of enhanced AR expression and DNA binding. Importantly, the AR was also found to reverse the inhibitory effect of the antioestrogen fulvestrant on BrCa proliferation. RNA-Seq analysis showed that the AR induces pathways linked to cellular proliferation, and becomes transcriptionally more active when ERα is inhibited by fulvestrant. Analysis of the transcriptional activity of AR mutants, identified in BrCa patients, showed that some mutations affect the transcriptional activity of the AR, and AR-ERα crosstalk. The data demonstrates that the role of the AR in BrCa is complex and that targeting both receptors may have a more clinically favourable outcome, and reduce therapy resistance in patients.