MMP1 expression is activated by Slug and enhances multi-drug resistance (MDR) in breast cancer

Ching Ju Shen, Yu Ling Kuo, Chien Chung Chen, Ming Jenn Chen, Ya Min Cheng

研究成果: Article

13 引文 斯高帕斯(Scopus)

摘要

High matrix metalloproteinase 1 (MMP1) expression is associated with enhanced breast cancer growth and metastasis and also might predict poor prognosis. In this study, we further investigated the functional role of MMP1 and how it is upregulated in multi-drug resistant (MDR) breast cancer cells. By retrieving microarray data in GEO datasets and the survival data in the Kaplan Meier plotter, we observed that MMP1 is significantly upregulated in MCF-7/ADR cells compared to the parental MCF-7 cells, while high MMP1 expression is associated with worse overall survival (OS) and recurrence free survival (RFS) in breast cancer patients after systematic therapy. Functional studies showed that MMP1 overexpression significantly reduced the drug sensitivity in MCF-7 cells, while MMP1 knockdown substantially enhanced the sensitivity in MCF-7/ADR cells. By performing western blotting and immunofluorescent staining, we confirmed that MCF-7/ADR cells had enhanced mesenchymal properties than MCF-7 cells. In MCF-7 cells, enforced Slug expression resulted in significant MMP1 upregulation, while in MCF-7/ADR cells, Slug knockdown led to reduced MMP1 expression. By performing bioinformatic analysis, we observed that the promoter of MMP1 has three putative Slug binding sites. The following dual luciferase assay and ChIP-qPCR verified these three binding sites. Therefore, we infer that Slug enhances MMP1 transcription via directly binding to the promoter region in breast cancer cells, which is a previously unrecognized mechanism in the development of MDR.

原文English
文章編號e0174487
期刊PloS one
12
發行號3
DOIs
出版狀態Published - 2017 三月

    指紋

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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