Breast cancer overwhelmingly affects women (approximately 1000:1 ratio of women to men), with around 80% of cases driven by oncogenic oestrogen receptor-α (ERα) activity. Endocrine therapy, including surgical removal of ovaries (oophorectomy), aromatase inhibitors or pharmaceutical ERα ablation, has long been the cornerstone of treatment in ER+ breast cancer. Although effective in localized disease, it fails against metastatic endocrine-resistant breast cancer, the primary cause of mortality. This underscores the need for new treatment strategies beyond targeting oestrogen and ERα. In this context, the androgen receptor (AR), a key player in breast cancer biology, has long been overlooked. In the normal breast, oestrogen drives mammary gland growth, while androgens counterbalance it. The majority of ER+ breast cancers also express AR, and treatment strategies adapted from prostate cancer using AR antagonists have failed in clinical trials. Considering the role of AR in normal breast biology, this might have been the wrong approach. Instead of blocking AR, does it need to be activated?

Hickey et al. tackled this question, conducting a large-scale preclinical study using cell lines and patient-derived breast cancer models, including endocrine-resistant ones with ESR1 and CCND1 amplification or mutations. The authors used ChIP–seq (chromatin immunoprecipitation followed by sequencing) to map genome-wide interactions of AR and ERα with chromatin under different hormonal conditions. When AR was activated with dihydrotestosterone (DHT) and ERα with oestradiol, AR hijacked the transcriptional program of ERα by sequestering shared transcriptional coactivators such as SRC3 and p300 from ERα genomic sites. In doing so, AR effectively displaced ERα from target chromatin, shutting down ERα-driven tumour growth.

This explained why past AR antagonists such as enzalutamide had failed; blocking AR removed a crucial tumour suppressor. However, AR agonists such as DHT or the selective, non-virilizing agonist enobosarm suppressed tumour growth in ER+ breast cancer models.

Encouragingly, a phase II clinical trial (NCT02463032) confirmed that enobosarm was not only effective but also well tolerated in women who had exhausted standard endocrine therapies.

The study by Hickey et al. represents a paradigm shift, highlighting how the intricate cross-talk between steroid receptors, beyond a singular focus on ERα, can be strategically leveraged for breast cancer therapy. It also underscores the need for further research into the dynamic hormonal landscape in women, particularly the substantial hormonal shifts post-menopause, which may alter transcriptional programs and influence responses to endocrine therapy.

“blocking AR removed a crucial tumour suppressor”

My lab explores transcriptional mechanisms of nuclear receptors and, inspired by the study discussed here, we are examining the ERα–AR interplay across a range of oestradiol-to-DHT ratios to mimic shifts from pre- to post-menopause. Our initial findings suggest that ligand balance shapes receptor interactions, highlighting the need to consider ligand ratios for effective therapy.