Membrane-initiated estradiol signaling of epithelial-mesenchymal transition-associated mechanisms through regulation of tight junctions in human breast cancer cells.
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.
Department of Biology of Reproduction, Universidad Autonoma Metropolitana (UAM), 09310, Mexico City, Mexico.
Javier E
JE
Jiménez-Salazar
Pedro
P
Posadas-Rodríguez
Roberto C
RC
Lazzarini-Lechuga
Armando
A
Luna-López
Alejandro
A
Zentella-Dehesa
Luis E
LE
Gómez-Quiroz
Mina
M
Königsberg
Guadalupe
G
Domínguez-Gómez
Pablo
P
Damián-Matsumura
D021581:Active Transport, Cell Nucleus; D001943:Breast Neoplasms / Q000473:pathology*; D000081247:CSK Tyrosine-Protein Kinase; D015820:Cadherins / Q000032:analysis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D011960:Receptors, Estrogen / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D019108:Tight Junctions / Q000502:physiology*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D015820:Cadherins; D011960:Receptors, Estrogen; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D004958:Estradiol; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human