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KMID : 1134120230260050446
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Journal of Breast Cancer
2023 Volume.26 No. 5 p.446 ~ p.460
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Estradiol-Induced Epithelial to Mesenchymal Transition and Migration Are Inhibited by Blocking c-Src Kinase in Breast Cancer Cell Lines
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Javier E. Jimenez-Salazar
Rene M. Rivera-Escobar
Rebeca Damian-Ferrara
Juan Maldonado-Cubas
Catalina Rincon-Perez
Rosario Tarrago-Castellanos
Pablo Damian-Matsumura
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Abstract
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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 (E2) 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 E2, through increasing the ability of MCF-7 and T47-D cells, which express estrogen receptor alpha (ERα), to migrate and invade before they become metastatic.
Results : Treatment with E2 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 μM 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, E2 binds to ERα, 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 E2 enhance EMT and migration, through c-Src activation, in human breast cancer cells that express ERα and become potential therapeutic targets.
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KEYWORD
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Adherens Junctions, Receptors, Estrogen, Signal Transduction, Src-Family Kinases, Tight Junctions
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