Estradiol-Induced Epithelial to Mesenchymal Transition and Migration Are Inhibited by Blocking c-Src Kinase in Breast Cancer Cell Lines

Purpose: The epithelial-to-mesenchymal transition (EMT) is the main event that favors cell migration and metastasis in breast cancer. Previously, we demonstrated that 1 nM estradiol (E-2) promotes EMT, induced by c-Src kinase, causing changes in the localization of proteins that compose the tight junction (TJ) and adherens junction (AJ). Methods: The present work highlights the central role of c-Src in the initiation of metastasis, induced by E-2, through increasing the ability of MCF-7 and T47-D cells, which express estrogen receptor alpha (ER alpha), to migrate and invade before they become metastatic. Results: Treatment with E-2 can activate two signaling pathways, the first one by the phosphorylated c-Src (p-Src) which forms the p-Src/E-cadherin complex. This phenomenon was completely prevented by incubation with a selective inhibitor of c-Src (5 mu M PP2). p-Src then promotes the downregulation of E-cadherin and occludin, which are epithelial phenotype marker proteins of the AJ and TJ, respectively. In the second pathway, E-2 binds to ER alpha, creating a complex that translocates to the nucleus, inducing the synthesis of SNAIL1 and N-cadherin proteins, markers of the mesenchymal phenotype. Both processes increased the migratory and invasive capacities of both cell lines. Conclusion: The present study demonstrate that E-2 enhance EMT and migration, through c-Src activation, in human breast cancer cells that express ER alpha and become potential therapeutic targets.