title: Estrogen adversely affects the prognosis of patients with lung adenocarcinoma.
abstract: Estrogen has been postulated to contribute to the development and progression of lung cancer. We examined the epidemiologic evidence, explored the characteristics of estrogen receptors (ER) in lung adenocarcinoma, and investigated the effect of estrogen on lung cancer cell migration, including the signaling pathway involved. For epidemiologic evidence, a total of 1434 consecutive non-small cell lung cancer patients who underwent standardized staging and homogenous treatment were prospectively enrolled from January 2002 to December 2008, and followed until December 2012. The possible prognostic factors to be analyzed included stage, age, gender, menopausal status, smoking history and histology. For laboratory study, lung cancer cell lines A549 and PE089 and malignant pleural effusions from the patients with lung adenocarcinoma were used. We found that the premenopausal patients had more advanced disease and a shorter survival among the never-smoking female patients with lung adenocarcinoma. ERβ was the predominant ER in the lung cancer cell lines. 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. Our results suggest that estrogen adversely affects the prognosis of patients with lung adenocarcinoma. Osteopontin contributed to the cross-talk between ER and EGFR signaling pathways. Estrogen, with its receptor, has the potential to be a prognosticator and a therapeutic target in lung cancer.
authors.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.
authors.forename: Li-Han
authors.initials: LH
authors.lastname: Hsu
authors.forename: Ko-Jiunn
authors.initials: KJ
authors.lastname: Liu
authors.forename: Ming-Fang
authors.initials: MF
authors.lastname: Tsai
authors.forename: Chang-Ru
authors.initials: CR
authors.lastname: Wu
authors.forename: An-Chen
authors.initials: AC
authors.lastname: Feng
authors.forename: Nei-Min
authors.initials: NM
authors.lastname: Chu
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Kao
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D004958:Estradiol / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000502:physiology*; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D016066:Pleural Effusion, Malignant / Q000378:metabolism; D011379:Prognosis; D011446:Prospective Studies; D011799:Quinazolines / Q000494:pharmacology; D015533:Transcriptional Activation
chemical_list: D000970:Antineoplastic Agents; D047629:Estrogen Receptor beta; D004967:Estrogens; D011799:Quinazolines; D053495:Osteopontin; D004958:Estradiol; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Epidermal growth factor receptor; estrogen; estrogen receptor; lung cancer; osteopontin