Extracellular Matrix Derived from High Metastatic Human Breast Cancer Triggers Epithelial-Mesenchymal Transition in Epithelial Breast Cancer Cells through αvβ3 Integrin

• Published in: International journal of molecular sciences Vol. 21; no. 8; p. 2995
• Main Authors: M Brandão-Costa, Renata, Helal-Neto, Edward, M Vieira, Andreza, Barcellos-de-Souza, Pedro, Morgado-Diaz, Jose, Barja-Fidalgo, Christina
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23.04.2020; MDPI
• Subjects: Activation; AKT protein; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell adhesion & migration; Cell culture; Cell differentiation; Cell Line, Tumor; Cell Movement; Cell Proliferation; Crosstalk; disintegrin; E-cadherin; Epithelial cells; epithelial-mesenchymal transition; Epithelial-Mesenchymal Transition - genetics; Extracellular matrix; Extracellular Matrix - metabolism; Female; Genotype & phenotype; Glycoproteins; Humans; Integrin alphaVbeta3 - genetics; Integrin alphaVbeta3 - metabolism; integrin signaling; Kinases; Mesenchyme; Metastases; Metastasis; Morphology; Nuclear transport; Phenotypes; Phosphorylation; Protein Binding; Proteins; Signal Transduction; Smad2 protein; Smad4 protein; Transforming Growth Factor beta - metabolism; Tumor cells; Tumors; breast cancer; disintegrin; epithelial-mesenchymal transition; integrin signaling; extracellular matrix
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21082995

Alterations in the composition and architecture of the extracellular matrix (ECM) can influence cancer growth and dissemination. During epithelial-mesenchymal transition (EMT), epithelial cells assume a mesenchymal cell phenotype, changing their adhesion profiles from cell-cell contacts to cell-matrix interactions, contributing to metastasis. Breast cancer cells present at different stages of differentiation, producing distinct ECMs in the same tumor mass. However, the contribution of ECM derived from metastatic tumor cells to EMT is unclear. Here, we showed the mechanisms involved in the interaction of MCF-7, a low-metastatic, epithelial breast cancer cell line, with the ECM produced by a high metastatic breast tumor cell, MDA-MB-231 (MDA-ECM). MDA-ECM induced morphological changes in MCF-7 cells, decreased the levels of E-cadherin, up-regulated mesenchymal markers, and augmented cell migration. These changes were accompanied by the activation of integrin-associated signaling, with increased phosphorylation of FAK, ERK, and AKT and activation canonical TGF-β receptor signaling, enhancing phosphorylation of SMAD2 and SMAD4 nuclear translocation in MCF-7 cells. Treatment with Kistrin (Kr), a specific ligand of integrin αvβ3 EMT induced by MDA-ECM, inhibited TGF-β receptor signaling in treated MCF-7 cells. Our results revealed that after interaction with the ECM produced by a high metastatic breast cancer cell, MCF-7 cells lost their characteristic epithelial phenotype undergoing EMT, an effect modulated by integrin signaling in crosstalk with TGF-β receptor signaling pathway. The data evidenced novel potential targets for antimetastatic breast cancer therapies.