MMP1 expression is activated by Slug and enhances multi-drug resistance (MDR) in breast cancer.
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.
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Gynecology and Obstetrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Ching-Ju
http://orcid.org/0000-0002-9975-4210
CJ
Shen
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Gynecology and Obstetrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Yu-Ling
YL
Kuo
Department of Plastic and Reconstruction Surgery, E-Da Hospital, Kaohsiung, Taiwan.
Chien-Chung
CC
Chen
Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan.|Department of Sports Management, College of Leisure and Recreation Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
Ming-Jenn
MJ
Chen
Department of Obstetrics and Gynecology, Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Ya-Min
YM
Cheng
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D053453:Caspase 9 / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D014158:Transcription, Genetic
C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D053453:Caspase 9; D020781:Matrix Metalloproteinase 1