Integrative miRNOMe profiling reveals the miR-195-5p-CHEK1 axis and its impact on luminal breast cancer outcomes

The luminal subtype (estrogen receptor-positive, ER+) is the most common and the most heterogeneous type of breast carcinoma (BC) in women. During our study, we determined expression levels of all microRNAs (miRNOMe) in 101 ER+ BC samples and identified 25 miRNAs being associated with proliferative markers. Using comprehensive in silico analyses we prioritized CHEK1, CDC25A, and CCNE1 as candidate genes affecting the proliferation of ER+ BC, with two microRNAs from the miR-497∼195 cluster identified as their potential regulators. In a cohort of 217 patients, we found a significant association between low expression of CHEK1 and prolonged relapse-free survival (RFS) in luminal BC patients treated with adjuvant chemotherapy. In patients with luminal A subtype treated with neoadjuvant therapy, the opposite role for RFS was seen for hsa-miR-195-5p. Subsequently, we confirmed the potency of hsa-miR-195-5p to inhibit the expression of CHEK1 in vitro. Moreover, the specific Chk1 inhibitor rabusertib (LY2603618) significantly enhanced the efficacy of doxorubicin in ER+ MCF-7 cell line. In summary, we have identified the association of a miRNA profile with highly proliferative luminal BCs and demonstrated the ability of hsa-miR-195-5p to inhibit CHEK1 expression in BC in vitro, underlining the importance of CHEK1 expression and its inhibition for prognosis and treatment of patients with luminal BCs. Expression levels of all miRNAs (miRNOMe) were detected in 101 luminal (ER+) early breast carcinoma samples.