Abstract
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.
Highlights
Chemotherapy is the major therapeutic strategy for advanced breast cancer
Matrix metalloproteinase 1 (MMP1) is upregulated in MCF-7/ADR cells compared to the parental MCF-7 cells
High MMP1 expression is associated with worse survival outcomes in breast cancer patients after systematic therapy
Summary
MMP1 activated by Slug enhances MDR in breast cancer resistance (MDR), which leads to therapeutic failure and cancer-related death [1,2,3]. Matrix metalloproteinase 1 (MMP1), which is known as interstitial collagenase and fibroblast collagenase is a member of the matrix metalloproteinases (MMPs) family [8]. Proteins in this family mainly participate in the breakdown of extracellular matrix both in normal physiological processes and disease processes [9]. The functional role of MMP1 in MDR breast cancer cells and whether other mechanisms are involved in its upregulation in the cells have not been fully understood
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