Targeting microRNA let-7b-5p-mediated aberrant androgen receptor signaling for prevention of hormone receptor-negative breast cancer.

Androgen receptor, the key mediator of the AR signaling pathway, is expressed in the majority of breast cancers and has been emerging as a potential target for treatment with encouraging results in preclinical and clinical trials. But whether AR plays a role in the preneoplastic context to serve as a target for breast cancer prevention is unknown. Our results showed upregulation of AR expression in the preneoplastic and preinvasive sublines of the MCF10A breast cancer progression model. Similarly, we observed a trend towards higher expression of AR in the tumors and matched histologically normal mammary tissues of TNBC-LAR patients compared to normal noncancer controls. Mechanistically, we identified AR as a novel gene target of tumor suppressor microRNA let-7b-5p, which directly binds the AR 3' untranslated region. Mirroring AR upregulation, there was a corresponding loss of let-7b-5p expression in tumors of TNBC patients. By targeting this aberrant let-7b-5p-mediated AR signaling pathway with AR inhibitor enzalutamide, the growth and survival of preneoplastic and preinvasive lesions were significantly reduced in cell line models. Overall, our study highlights the role of let-7b-5p-mediated aberrant AR signaling in breast tumorigenesis and as a potential target for prevention in populations at risk for hormone receptor-negative breast cancer.