The Role of Androgen Receptor Signalling in Endocrine Resistant Breast Cancer

Breast cancer (BCa) is the most prevalent cancer among women in the UK. The majority of BCas are endocrine sensitive and develop through the action of oestrogens, facilitated through the transcription factor Oestrogen Receptor alpha (ERα). Treatment for these patients usually involves endocrine therapies (Aromatase Inhibitors and antioestrogens), which are successful in many patients, but therapy resistance represents a major clinical issue. The Androgen Receptor (AR) is a transcription factor that is more highly expressed than ERα in BCa, and mediates the functions of androgens. In early forms of ERα-positive disease, AR is a positive indicator of prognostic outcome and suppresses ERα signalling. However, in ERα-negative disease AR has been demonstrated to drive cancer progression and recent evidence has suggested that AR can drive endocrine resistance. Reporter assays, gene expression analysis and Chromatin Immunoprecipitation assays demonstrated that AR and ERα inhibit each other’s activity and that antioestrogens can reverse this inhibition, resulting in an active AR. Importantly, long term colony formation assays demonstrated that androgen could induce anti-oestrogen resistant growth, but anti-androgens prevented this from developing. Co-treatment of tumours with anti-oestrogens and anti-androgens could therefore be a viable option to block this mechanism of resistance. Cell line models of endocrine resistant disease were used to investigate AR signalling in therapy resistance. The results demonstrated that AR levels were enhanced in several lines and that all cell lines were sensitive to androgen for growth. Importantly, anti-androgens could inhibit androgen-induced growth in all models. Anti-androgens could therefore also be a viable option for the treatment of tumours that have become resistant to endocrine therapies. This study therefore furthers our understanding of the role of the AR in BCa progression and suggests that it is a valid therapeutic target to prevent and/or treat endocrine resistant disease.