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MiR‐200c suppresses TGF‐β signaling and counteracts trastuzumab resistance and metastasis by targeting ZNF217 and ZEB1 in breast cancer
Author(s) -
Bai WenDong,
Ye XingMing,
Zhang MengYao,
Zhu HuaYu,
Xi WenJin,
Huang Xun,
Zhao Jiao,
Gu Bin,
Zheng GuoXu,
Yang AnGang,
Jia LinTao
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28782
Subject(s) - trastuzumab , metastasis , breast cancer , cancer research , gene silencing , medicine , signal transduction , microrna , transforming growth factor , cancer , biology , oncology , microbiology and biotechnology , gene , biochemistry
Resistance to trastuzumab and concomitantly distal metastasis are leading causes of mortality in HER2‐positive breast cancers, the molecular basis of which remains largely unknown. Here, we generated trastuzumab‐resistant breast cancer cells with increased tumorigenicity and invasiveness compared with parental cells, and observed robust epithelial–mesenchymal transition (EMT) and consistently elevated TGF‐β signaling in these cells. MiR‐200c, which was the most significantly downregulated miRNA in trastuzumab‐resistant cells, restored trastuzumab sensitivity and suppressed invasion of breast cancer cells by concurrently targeting ZNF217, a transcriptional activator of TGF‐β, and ZEB1, a known mediator of TGF‐β signaling. Given the reported backward inhibition of miR‐200c by ZEB1, ZNF217 also exerts a feedback suppression of miR‐200c via TGF‐β/ZEB1 signaling. Restoration of miR‐200c, silencing of ZEB1 or ZNF217 or blockade of TGF‐β signaling increased trastuzumab sensitivity and suppressed invasiveness of breast cancer cells. Therefore, our study unraveled nested regulatory circuits of miR‐200c/ZEB1 and miR‐200c/ZNF217/TGF‐β/ZEB1 in synergistically promoting trastuzumab resistance and metastasis of breast cancer cells. These findings provide novel insights into the common role of EMT and related molecular machinery in mediating the malignant phenotypes of breast cancers.