MiR-218 regulates cisplatin chemosensitivity in breast cancer by targeting BRCA1

Abstract

Cisplatin resistance presents a major challenge in the successful treatment of breast cancer, and its mechanism has not been documented well. In this study, to determine the relationship between chemotherapy resistance and microRNA (miRNA) expression during the development of cisplatin resistance in breast cancer, we used microRNA microarrays analysis successfully identified 19 miRNAs that were either overexpressed or underexpressed (8 upregulated and 11 downregulated) in the MCF-7 cell line and its cisplatin-resistant variant MCF-7/DDP. Among them, the miR-218 was most downregulated in cisplatin-resistant cell lines and identified that breast cancer 1 (BRCA1) was the cellular targets of miR-218. In vivo assay also demonstrated that restoring miR-218 expression in MCF-7/DDP cell line could sensitize cells against cisplatin, thereby increasing cisplatin-mediated tumor cell apoptosis and reducing DNA repair. Kaplan-Meier survival analysis indicated that patients with breast cancer display high levels of miR-218 and low levels of BRCA1 expression; these patients may gain the greatest benefits in terms of increased survival when treated with cisplatin. All of these results indicated that miR-218 has a significant function in the development of cisplatin resistance in breast cancer. Restoring miR-218 expression may constitute a novel therapeutic approach by which to increase cisplatin sensitivity in breast cancer.

miR-218 targets survivin and regulates resistance to chemotherapeutics in breast cancer

“…In addition, miR-218 has been found to modulate chemosensitivity in human gastric cancer cells [39], and restoration of miR-218 expression increases cisplatin sensitivity, and induces apoptosis, in cisplatinresistant MCF-7 cells by targeting BRCA1 [17]. We find that experimental overexpression of miR-218 in both MCF-7/A02 and CALDOX cells restores short-term sensitivity and long-term proliferation in the presence of doxorubicin and taxol.…”

“…Its down-regulation has been reported in several human malignancies, including cervical, gastric and colon cancer [12][13][14][15]. In breast cancer, BRCA1 and HoxB3 mRNAs are direct targets of miR-218 [16,17]. However, the functional role of miR-218 in breast cancer chemosensitivity remains to be characterized.…”

Usefulness of miRNA profiles for predicting pathological responses to neoadjuvant chemotherapy in patients with human epidermal growth factor receptor 2-positive breast cancer

“…Twenty-one miRNAs were differentially expressed between the non-pCR and pCR groups in the analysis of all 40 patients with HER2-positive breast cancer (Table III). Nine of these 21 miRNAs are reported to be associated with breast cancer (17)(18)(19)(20)(21)(22)(23)(24)(25). The other 12 miRNAs have no reported correlation with breast cancer.…”

“…For the luminal B-like (HER2-positive) subtype, 17 miRNAs were differentially expressed (Table IV), and nine of these 17 miRNAs are reported to be correlated with breast cancer (20)(21)(22)24,(26)(27)(28)(29)(30). For the HER2-positive (non luminal) subtype, 14 miRNAs were differentially expressed (Table V), and five of these are reported to be correlated with breast cancer (17,23,25,31,32). The miRNA expression profiles associated with pathological response differed completely between the HER2-positive (non luminal) and luminal B-like (HER2-positive) subtypes.…”

“…Downregulation of miR-106b involves bone metastasis of breast cancer with negative regulation of matrix metalloproteinase 2 (17). miR-218 was downregulated in cisplatin-resistant breast cancer cell lines and regulated chemosensitivity by targeting BRCA1 (23). miR-505 has been reported as a tumor-suppressive miRNA, and is inversely correlated with Akt3, which modulates drug sensitivity (25).…”