Membrane-initiated estradiol signaling of epithelial-mesenchymal transition-associated mechanisms through regulation of tight junctions in human breast cancer cells.

Abstract

Tumor cells utilize inappropriate epithelial-mesenchymal transition (EMT) mechanisms during the invasive process. It is becoming increasingly clear that estradiol (E2) induces breast cancer cell progression and enhances EMT; however, the mechanisms associated with this are unclear. We investigated the role of E2 on the expression and intracellular localization of the tight junction (TJ)-associated proteins, zonula occluden 1 (ZO-1), ZO-1-associated nucleic acid binding (ZONAB), and occludin, on the activation of c-Src and human epidermal growth factor receptor 2 (HER2) expression and cellular migration in the estrogen receptor (ER)-positive breast cancer cell lines, MCF-7 and T47D. We demonstrated that 1 nM E2 elicits c-Src activation after 15 min. The p-Src/ZO-1 complex led to ZO-1 and ZONAB disruption at the TJ and increased expression of HER2 mRNAs. These changes correlate with decreased expression of the epithelial markers occludin and CRB3 and increased synthesis of N-cadherin. This led to increased MCF-7 cell migration induced by E2, even in the presence of a cell proliferation inhibitor. Incubation with ICI 182,780 (Fulvestrant), an ER antagonist, precluded the effects of E2 on c-Src phosphorylation, p-Src/ZO-1 complex formation, ZO-1/ZONAB nuclear translocation, and migration of MCF-7 cells. Our findings suggest that E2 promotes TJ disruption during tumor progression and increases cell motility. We propose a novel pathway where estrogens promote EMT-associated mechanisms that possibly lead to metastasis.

• Authors: Javier E Jiménez-Salazar, Pedro Posadas-Rodríguez, Roberto C Lazzarini-Lechuga, Armando Luna-López, Alejandro Zentella-Dehesa, Luis E Gómez-Quiroz, Mina Königsberg, Guadalupe Domínguez-Gómez, Pablo Damián-Matsumura
• Journal: Hormones & cancer (Horm Cancer) Vol. 5 Issue 3 Pg. 161-73 (Jun 2014) ISSN: 1868-8500 [Electronic] United States
• PMID: 24771004 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• Receptors, Estrogen
• TJP1 protein, human
• Zonula Occludens-1 Protein
• Estradiol
• CSK Tyrosine-Protein Kinase
• src-Family Kinases
• CSK protein, human

Topics

• Active Transport, Cell Nucleus
• Breast Neoplasms (pathology)
• CSK Tyrosine-Protein Kinase
• Cadherins (analysis)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Epithelial-Mesenchymal Transition
• Estradiol (pharmacology)
• Female
• Humans
• Receptors, Estrogen (physiology)
• Signal Transduction (physiology)
• Tight Junctions (physiology)
• Zonula Occludens-1 Protein (metabolism)
• src-Family Kinases (metabolism)