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

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.

Prognostic value of two novel genes SNX10 and PTGDS for cervical squamous cell carcinoma: an integrated bioinformatic analysis

“…promoted the growth and metastasis of esophageal squamous cell carcinoma (42). It has also been identified that MMP1 participated in breast and ovarian cancer (43,44 (46). PLOD2 has been shown to play a role in cervical cancer (35) and renal cell carcinoma (47).…”

P4HA3 is Epigenetically Activated by Slug in Gastric Cancer and its Deregulation is Associated With Enhanced Metastasis and Poor Survival

“…Traditionally, Slug can negatively regulate the transcription of multiple genes by binding to E-box motifs in their promoters, such as E-cadherin 22 and Phosphatase and tensin homolog (PTEN). 23 Recent studies found that it can activate the transcription of hexokinase-2 and MMP1 by binding to their respective promoters in breast cancer 24 , 25 and can also activate ZEB1 expression in melanoma via promoter binding. 26 In GC, increased Slug expression has well-characterized oncogenic properties and also confers malignant behaviors to the cancers.…”

Cellular Plasticity in Breast Cancer Progression and Therapy

“…As a result, intercellular contacts and apical-basal polarity are lost, and tumor cell motility is enhanced via reorganization of the actin cytoskeleton and the intermediate filament network (Thiery et al, 2009;May et al, 2011). EMT-associated transcription factors can also stimulate secretion of gelatinases and matrix metalloproteinases (MMPs), leading to remodeling of the extracellular matrix (ECM) (Galindo-Hernandez et al, 2015;Shen et al, 2017). The induction of EMT in carcinomas can further increase tumor angiogenesis via enriching CSCs which possess the capacity to differentiate into endothelial cells and also upregulate the expression of the pro-angiogenic transcription factor VEGF-A (Fantozzi et al, 2014;Delgado-Bellido et al, 2017).…”