PARP inhibitor increases chemosensitivity by upregulating miR-664b-5p in BRCA1-mutated triple-negative breast cancer

Abstract

Abstract Emerging evidence has shown that adding poly(ADP-ribose) polymerase (PARP) inhibitors to chemotherapy regimens is superior to the control regimens alone in BRCA1-mutated triple-negative breast cancer (TNBC) patients, but their underlying mechanisms have not been fully elucidated. In this study, using miRNA microarray analysis of two BRCA1-mutated TNBC cell lines, we found that miR-664b-5p expression was increased after adding a PARP inhibitor, olaparib, to a carboplatin (CBP) plus gemcitabine (GEM) therapy regimen. Functional assays showed miR-664b-5p overexpression inhibited proliferation, migration and invasion in BRCA1-mutated TNBC cells. CCNE2 was identified as a novel functional target of miR-664b-5p, and CCNE2 knockdown revealed effects similar to those observed with miR-664b-5p overexpression. Both CCNE2 knockdown and miR-664b-5p overexpression significantly increased the chemosensitivity of BRCA1-mutated TNBC cells. In addition, in vivo studies indicated that miR-664b-5p inhibited tumour growth compared with the control in tumour xenograft models, and we also found that CCNE2 expression was inversely correlated with miR-664b-5p expression in 90 TNBC patient samples. In conclusion, miR-664b-5p functions as a tumour suppressor and has an important role in the regulation of PARP inhibitors to increase chemosensitivity by targeting CCNE2. This may be one of the possible mechanisms by which PARP inhibitors increase chemosensitivity in BRCA1-mutated TNBC.