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 high expression of CHEK1 and shorter relapse-free survival (RFS) in luminal BC patients treated with adjuvant chemotherapy, especially in patients with luminal A subtype. In patients treated with neoadjuvant therapy, the opposite role for RFS was observed 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 both ER+ and ER- cell lines. In summary, we have identified the association of a specific 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.

Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Comprehensive Cancer Center of Hospital AGEL Novy Jicin Czech Republic

Department of Biochemistry Cell and Molecular Biology 3rd Faculty of Medicine Charles University Prague Czech Republic

Department of Oncology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Surgery 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

EUC Hospital Zlin and Tomas Bata University in Zlin Czech Republic

MEDICON a s Prague Czech Republic

Toxicogenomics Unit National Institute of Public Health Prague Czech Republic

Unilabs Pathology k s Prague Czech Republic

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