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Open Access Highly Accessed Research article

Epigenetic silencing of miR-375 induces trastuzumab resistance in HER2-positive breast cancer by targeting IGF1R

Xing-Ming Ye12, Hua-Yu Zhu1, Wen-Dong Bai3, Ting Wang1, Lei Wang1, Ying Chen2, An-Gang Yang3* and Lin-Tao Jia1*

Author Affiliations

1 State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an 710032, China

2 Fujian Provincial Cancer Hospital, the Teaching Hospital of Fujian Medical University, Fuzhou 350014, China

3 Department of Immunology, Fourth Military Medical University, Xi’an 710032, China

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BMC Cancer 2014, 14:134  doi:10.1186/1471-2407-14-134

Published: 26 February 2014

Abstract

Background

Resistance to humanized monoclonal erbB2/HER2 antibody, trastuzumab (Herceptin), has become a pivotal obstacle for targeted therapy of HER2-positive breast cancers. The activation of alternative growth factor receptors, in particular, the insulin-like growth factor 1 receptor (IGF1R), represents a common feature of trastuzumab-refractory cells; however, the underlying mechanism remains elusive.

Methods

Trastuzumab-resistant breast cancer SKBr-3 cells were generated by long-term in vitro culture of SKBr-3 cells in the presence of trastuzumab. Among the differentially expressed microRNAs (miRNAs) screened by microarray analysis, candidate miRNA(s) predicted to target IGF1R was studied for its role in conferring trastuzumab resistance. The mechanism underlying decreased expression of IGF1R-targeted miRNA in refractory cells was also addressed.

Results

miR-375, which was downregulated and predicted to target IGF1R in trastuzumab-resistant HER2-positive breast cancer cells, could indeed inhibit the cellular luciferase activity in a reporter construct containing the 3′-UTR of IGF1R. Overexpression of miR-375 restored the sensitivity of cells to trastuzumab, while inhibition of miR-375 conferred trastuzumab resistance on HER2-positive breast cancer cells. Blockade of DNA methylation and histone deacetylation restored the expression of miR-375 in trastuzumab-resistant cells. A reverse correlation between the levels of miR-375 and IGF1R was validated in clinical breast cancers.

Conclusions

Epigenetic silencing of miR-375 causes the upregulation of IGF1R, which at least partially underlies trastuzumab resistance of breast cancer cells. Our study has implications for miR-375 as a potential target in combination with trastuzumab for treating HER2-positive breast cancers.

Keywords:
miR-375; Insulin-like growth factor 1 receptor; Trastuzumab resistance; erbB2/HER2; Breast cancer