Estrogen adversely affects the prognosis of patients with lung adenocarcinoma.
Bottom Line: We found that the premenopausal patients had more advanced disease and a shorter survival among the never-smoking female patients with lung adenocarcinoma.We proposed a different pathway that estrogen upregulated the expression of osteopontin and then promoted cell migration through αvβ3 integrin binding and activated MEK-ERK signaling pathway, which is a common downstream pathway with epidermal growth factor receptor (EGFR) activation.An additive effect of ER antagonists and EGFR antagonists on the inhibition of cell migration was also noted.
Affiliation: Division of Pulmonary and Critical Care Medicine, Sun Yat-Sen Cancer Center, Taipei, Taiwan; Department of Medicine, National Yang-Ming University Medical School, Taipei, Taiwan.Show MeSH
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Mentions: To test whether OPN was a downstream molecule of the estrogen signaling pathway and whether it contributed to cell migration, the expression levels of the OPN gene were quantified. A 2.2-fold increase in OPN mRNA level was detected in the E2-treated A549 cells (Fig.4a,b). The protein levels of OPN also increased in the medium cultured with E2 (Fig.4c). Both the E2-induced OPN expressions were reduced in the presence of tamoxifen (Fig.4a–c). OPN-induced cell migration and ERK phosphorylation were significantly inhibited by U0126 (MAP kinase/MEK inhibitor) (Fig.4d,e). The integrin receptor αvβ3 interacts with OPN via the arginine-glycine-aspartate (RGD) motif. The anti-αvβ3 Ab significantly inhibited OPN-induced cell migration and E2-stimulated or EGF-stimulated cell migration (Fig.4f). These results suggested that estrogen induced OPN expression and promoted cancer cell migration through αvβ3 integrin binding and MEK/ERK signaling, and implied that OPN-αvβ3 integrin-induced cell migration was involved in the activation of ER and EGFR signaling pathways.
Affiliation: Division of Pulmonary and Critical Care Medicine, Sun Yat-Sen Cancer Center, Taipei, Taiwan; Department of Medicine, National Yang-Ming University Medical School, Taipei, Taiwan.