Androgen Receptor Functions as a Tumor Suppressor in ER⁺ Breast Cancer

Estrogen receptor (ER) signaling drives the majority of breast cancers. However, resistance to ER-targeted (endocrine) therapy contributes substantially to ER⁺ breast cancer mortality, highlighting a need for new strategies that enhance therapeutic response or overcome resistance. Therapies targeting androgen receptor (AR) have gained interest, but conflicting studies have obscured the role of AR. To clarify the function of AR in ER⁺ breast cancer, Hickey and colleagues analyzed clinical data and discovered AR was associated with breast cancer–specific survival and predicted response to endocrine therapy. To determine whether AR activity could inhibit ER-driven growth, a patient-derived explant model was treated with estrogen and androgen, revealing that AR activation decreased proliferative index and negatively correlated with cell cycle regulation signatures. Mechanistic studies in estrogen-dependent breast cancer cell lines showed that treatment with estrogen and androgen altered the chromatin distribution of ER and its coactivators. Specifically, chromatin immunoprecipitation sequencing defined ER and AR binding sites and indicated that AR associated with ER on chromatin, redistributing ER away from loci associated with ER-regulated cell cycle genes and toward androgen response elements. In addition, AR activation displaced p300, an enzyme required to acetylate histone 3 at lysine residue 27 (H3K27ac) at transcriptionally active enhancers, and SRC3, a necessary factor for recruitment of p300 by ER, suggesting that AR inhibited ER target transcription by sequestering ER interactors. In xenograft models of endocrine resistance, AR agonism significantly decreased tumor growth. AR agonists also reduced in vitro growth and colony formation and in vivo tumor growth in the context of CDK4/6 inhibition, an emerging standard of care in combination with endocrine therapy. Lastly, using in vivo transcriptomic data, an AR-activity gene signature was created that had significant prognostic power in patient data. In summary, these studies reveal AR as an inhibitor of ER signaling and propose AR agonism as a rational therapeutic strategy in ER⁺ breast cancer.

Hickey TE, Selth LA, Chia KM, Laven-Law G, Milioli HH, Roden D, et al. The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer. Nat Med 2021 Jan 18 [Epub ahead of print].

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