miRNA-34a is associated with docetaxel resistance in human breast cancer cells

Abstract

Docetaxel is a chemotherapy drug to treat breast cancer, however as with many chemotherapeutic drugs resistance to docetaxel occurs in 50% of patients, and the underlying molecular mechanisms of drug resistance are not fully understood. Gene regulation through microRNAs (miRNA) has been shown to play an important role in cancer drug resistance. By directly targeting mRNA, miRNAs are able to inhibit genes that are necessary for signalling pathways or drug induced apoptosis rendering cells drug resistant. This study investigated the role of differential miRNA expression in two in vitro breast cancer cell line models (MCF-7, MDA-MB-231) of acquired docetaxel resistance. MiRNA microarray analysis identified 299 and 226 miRNAs altered in MCF-7 and MDA-MB-231 docetaxel-resistant cells, respectively. Docetaxel resistance was associated with increased expression of miR-34a and miR-141 and decreased expression of miR-7, miR-16, miR-30a, miR-125a-5p, miR-126. Computational target prediction revealed eight candidate genes targeted by these miRNAs. Quantitative PCR and western analysis confirmed decreased expression of two genes, BCL-2 and CCND1, in docetaxel-resistant cells, which are both targeted by miR-34a. Modulation of miR-34a expression was correlated with BCL-2 and cyclin D1 protein expression changes and a direct interaction of miR-34a with BCL-2 was shown by luciferase assay. Inhibition of miR-34a enhanced response to docetaxel in MCF-7 docetaxel-resistant cells, whereas overexpression of miR-34a conferred resistance in MCF-7 docetaxel-sensitive cells. This study is the first to show differences in miRNA expression, in particular, increased expression of miR-34a in an acquired model of docetaxel resistance in breast cancer. This serves as a mechanism of acquired docetaxel resistance in these cells, possibly through direct interactions with BCL-2 and CCND1, therefore presenting a potential therapeutic target for the treatment of docetaxel-resistant breast cancer.

GATA3 mutations define a unique subtype of luminal‐like breast cancer with improved survival

“…First, as a transcription factor, GATA3 induces a variety of genes during luminal differentiation, some of which play significant roles in chemoresistance, including trefoil factor 1, 24 phosphoserine aminotransferase 1, 25 anterior gradient 2 homolog, 26 and cyclin D1. 27,28 Mutations of GATA3 (especially in the zinc-finger region) might result in functional haploinsufficiency and downregulation of the expression level of these genes. However, the precise mechanism of the sensitivity of GATA3-mutant tumors to chemotherapy remains to be investigated.…”

MicroRNA-30a Sensitizes Tumor Cells to cis-Platinum via Suppressing Beclin 1-mediated Autophagy

“…All synthetic RNA molecules, including pre-miR-30a molecular, anti-miR-30a antisense oligonucleotide, and scrambled negative control oligonucleotides (miR-NC, pre-nc RNA, and anti-ncRNA) were purchased from Invitrogen. The antibodies (20) against LC3, beclin 1, and GAPDH were obtained from Santa Cruz Biotechnology (Santa Cruz, California).…”

“…Recently, miRNAs have been linked to cell chemosensitivity in different cancer cells. For example, miR-34a directly affects cell chemosensitivity in Ewing's sarcoma (19) and breast cancer cells (20). miR-21 plays a role in chemosensitivity in bladder (21) and pancreatic cancer (22), and the expression of miR-140 is associated with chemosensitivity in osteosarcoma tumor xenografts (23).…”

Downregulation of microRNA-17-5p inhibits drug resistance of gastric cancer cells partially through targeting p21

“…The development of drug resistance in various types of cancer cells has been reported to be associated with a reduced susceptibility to drug-induced apoptosis, which is partially due to the overexpression of anti-apoptotic proteins (5,12). miRNAs have been shown to perform a role in the initiation of cancer, tumor progression and sensitivity to treatment (13,14). Current studies suggest that miRNAs also perform important roles in mediating resistance to chemotherapy (11,15).…”