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.

Abstract. Cervical cancer is the most common malignancy in females worldwide. This study investigated the prevalence of the E6/E7 oncoproteins of human papillomavirus (HPV) type 16, which are important in fibroblast growth factor (FGF) 2-and 4-induced epithelial-mesenchymal transition (EMT) and cervical tumorigenesis. We investigated the functional interaction between HPV16 E6/E7-transfected Cx cells (CxWJ cells) and treatment with FGF2 and 4, according to the expression of α-smooth muscle actin (α-SMA), vimentin and E-cadherin protein as well as cell growth and invasive ability. The results showed the upregulation of α-SMA and vimentin and the downregulation of E-cadherin protein expression in CxWJ cells. HPV16 E6/E7 infection partially repressed proliferation, but not the invasive ability of FGF2 or FGF4 stimulation in cervical cancer cells (CxWJ cells). These data provide evidence of a functional interaction between HPV16 E6/E7 and FGFs 2 and 4, suggesting that cooperative stimulation of HPV E6/E7 and FGFs activated in human cervical cancer cells is required to completely overcome the oncogenic function associated with the development of cervical epithelial-mesenchymal transition and tumorigenesis.

No abstract