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

## TL;DR

The study finds that miR-195-5p regulates CHEK1, a gene linked to poor outcomes in luminal breast cancer, and that inhibiting CHEK1 improves chemotherapy effectiveness.

## Contribution

Identifies miR-195-5p as a regulator of CHEK1 and shows CHEK1 inhibition enhances chemotherapy in breast cancer.

## Key findings

- High CHEK1 expression correlates with worse relapse-free survival in luminal breast cancer patients.
- miR-195-5p inhibits CHEK1 expression in breast cancer cells in vitro.
- CHEK1 inhibition with rabusertib improves doxorubicin efficacy in breast cancer cell lines.

## Abstract

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.

In luminal (ER+) breast carcinoma (BC), miRNA profiling identified miR‐195‐5p as a key regulator of proliferation that targets CHEK1, CDC25A, and CCNE1. High CHEK1 expression correlates with worse relapse‐free survival after chemotherapy, especially in patients with luminal A subtype. miR‐195‐5p inhibits CHEK1 in vitro, and CHEK1 inhibition by rabusertib enhances doxorubicin efficacy, highlighting CHEK1 as a prognostic and therapeutic target.