Regulatory Interplay between miR-181a-5p and Estrogen Receptor Signaling Cascade in Breast Cancer

SIMPLE SUMMARY: Despite huge efforts in breast cancer care programs, patient’s survival rates greatly vary. Differences in response to therapy still represent the major challenge for clinicians and biologists. Define new anticancer mechanisms and innovative predictors for resistance could be a valid strategy to permanently defeat breast cancer. Here we propose the epigenetic based reprogramming of breast cancer, which leverages on the crosstalk between miR-181a-5p and Estrogen Receptor α. This simultaneously approach allows to induce miR-181a-5p and reduce the receptor expression, blocking the estrogen-dependent proliferative pathway underlying breast cancer progression. Since the epigenetic approach insists on transcriptional regulation, it is mostly independent of the acquired resistance mechanisms typically induced by prolonged endocrine therapy and therefore can be used as a sensitizer, neoadjuvant, or in combination with the standard in care treatments against breast cancer. ABSTRACT: The efficacy and side effects of endocrine therapy in breast cancer (BC) depend largely on estrogen receptor alpha (ERα) expression, the specific drug administered, and treatment scheduling. Although the benefits of endocrine therapy outweigh any adverse effects in the initial stages of BC, later- or advanced-stage tumors acquire resistance to treatments. The mechanisms underlying tumor resistance to therapy are still not well understood, posing a major challenge for BC patient care. Epigenetic regulation and miRNA expression may be involved in the switch from a treatment-sensitive to a treatment-resistant state and could provide a valid therapeutic strategy for ERα negative BC. Here, a hybrid lysine-specific histone demethylase inhibitor, MC3324, displaying selective estrogen receptor down-regulator-like activities in BC, was used to highlight the interplay between epigenetic and ERα signaling. MC3324 anticancer action is mediated by microRNA (miRNA) expression regulation, indicating an innovative function for this molecule. Integrated analysis suggests a crosstalk between estrogen signaling, ERα interactors, miRNAs, and their putative targets. Specifically, miR-181a-5p expression is regulated by MC3324 and has an impact on cellular levels of ERα. A comparison of breast tumor versus healthy mammary tissues confirmed the important role of miR-181a-5p in ERα regulation and points to its putative predictive function in BC therapy.