Abstract
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.
Highlights
Breast cancer is a heterogeneous disease with a variety of clinical and histological forms
We used a natural 3D matrix produced by highly metastatic breast cancer cells (MDA-MB-231) to investigate how it would affect the phenotype of non-metastatic MCF-7 cells, focusing on its capacity to induce epithelial to mesenchymal transition (EMT)
We showed that the interaction with the extracellular matrix produced by high metastatic breast cancer cells, MDA-MB-231, is able to induce EMT in MCF-7 cells, an epithelial-type breast cancer cell, increasing mesenchymal marker expression, modifying cell phenotype, and stimulating cell migration
Summary
Breast cancer is a heterogeneous disease with a variety of clinical and histological forms. While the canonical pathway is initiated by the phosphorylation of the cytoplasmic signaling molecules, SMAD2 is followed by recruitment and activation of R-SMAD (SMAD3 associated with SMAD2). This complex is phosphorylated and associates with SMAD4 through the MH2 domain, triggering its translocation to the nucleus. These two signaling pathways regulate the transcription of different genes that culminate in the characteristic morphological and functional changes of EMT [7,8]
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