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Breast Cancer Research
Published in: Breast Cancer Research 1/2019

Open Access 01-12-2019 | Breast Cancer | Research article

Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51

Authors: Jung Ok Lee, Min Ju Kang, Won Seok Byun, Shin Ae Kim, Il Hyeok Seo, Jeong Ah. Han, Ji Wook Moon, Ji Hae Kim, Su Jin Kim, Eun Jung Lee, Serk In Park, Sun Hwa Park, Hyeon Soo Kim

Published in: Breast Cancer Research | Issue 1/2019

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Abstract

Background

Chemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for TNBC treatment. Whether metformin enhances the anticancer effects of cisplatin and prevents cisplatin resistance in TNBC cells has not been reported.

Methods

Cell viability, wounding healing, and invasion assays were performed on Hs 578T and MDA-MB-231 human TNBC cell lines to demonstrate the anticancer effects of combined cisplatin and metformin treatment compared to treatment with cisplatin alone. Western blotting and immunofluorescence were used to determine the expression of RAD51 and gamma-H2AX. In an in vivo 4T1 murine breast cancer model, a synergistic anticancer effect of metformin and cisplatin was observed.

Results

Cisplatin combined with metformin decreased cell viability and metastatic effect more than cisplatin alone. Metformin suppressed cisplatin-mediated RAD51 upregulation by decreasing RAD51 protein stability and increasing its ubiquitination. In contrast, cisplatin increased RAD51 expression in an ERK-dependent manner. In addition, metformin also increased cisplatin-induced phosphorylation of γ-H2AX. Overexpression of RAD51 blocked the metformin-induced inhibition of cell migration and invasion, while RAD51 knockdown enhanced cisplatin activity. Moreover, the combination of metformin and cisplatin exhibited a synergistic anticancer effect in an orthotopic murine model of 4T1 breast cancer in vivo.

Conclusions

Metformin enhances anticancer effect of cisplatin by downregulating RAD51 expression, which represents a novel therapeutic target in TNBC management.
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Metadata
Title
Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51
Authors
Jung Ok Lee
Min Ju Kang
Won Seok Byun
Shin Ae Kim
Il Hyeok Seo
Jeong Ah. Han
Ji Wook Moon
Ji Hae Kim
Su Jin Kim
Eun Jung Lee
Serk In Park
Sun Hwa Park
Hyeon Soo Kim
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2019
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-019-1204-2

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