title: ERα phenotype, estrogen level, and benzo[a]pyrene exposure modulate tumor growth and metabolism of lung adenocarcinoma cells.
abstract: Women have a higher risk of lung adenocarcinoma than men, suggesting that estrogen pathway may be involved in the pathogenesis of this cancer. This study was designed to determine whether ERα expression, estrogen levels, and endocrine disruptor exposure would influence tumor growth of lung adenocarcinoma cells using a xenograft model in which human lung adenocarcinoma cells with and without transgenic ERα expression were transplanted into female nude mice. Results showed that estrogen promoted tumor growth of ERα(+) lung adenocarcinoma cells but inhibited that of ERα(-) lung adenocarcinoma cells. Endocrine disruptor benzo[a]pyrene stimulated ERα(-) tumor growth dose dependently. Either of ovariectomy and ERα expression abolished the tumor growth-promoting effect of benzo[a]pyrene. The high CYP1B1/CYP1A1 and low COMT/CYP1B1 expression ratios detected in ERα(+) tumors suggested an accumulation of 4-hydroxyestradiol metabolite under high body estrogen, whereas comparable CYP1A1 and CYP1B1 expression plus estrogen-inducible COMT expression might favor the formation of 2-methoxyestradiol in ERα(-) tumors. Inhibition of estrogen on ERα(-) tumor growth might be partly attributable to the anti-proliferative action of 2-methoxyestradiol. Benzo[a]pyrene increased expression of CYP1B1 over CYP1A1 and suppressed estrogen-induced COMT up-regulation in ERα(-) tumor cells, probably switching estrogen metabolism to 4-hydroxyestradiol formation and removing the inhibition of 2-methoxyestradiol on ERα(-) tumors. ERα inhibited AhR from up-regulating CYP1 in response to benzo[a]pyrene exposure, but it increased angiogenic VEGF-A expression with body estrogen levels. Estrogen might increase ERα(+) lung adenocarcinoma growth by up-regulating cancer-related ERα target gene expression.
authors.affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan, ROC.
authors.forename: Susana
authors.initials: S
authors.lastname: Lin
authors.forename: Chun-Ju
authors.initials: CJ
authors.lastname: Lin
authors.forename: Dennis P H
authors.initials: DP
authors.lastname: Hsieh
authors.forename: Lih-Ann
authors.initials: LA
authors.lastname: Li
mesh_terms: D000077584:2-Methoxyestradiol; D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001564:Benzo(a)pyrene / Q000633:toxicity*; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D002393:Estrogens, Catechol; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010052:Ovariectomy; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D002393:Estrogens, Catechol; D001564:Benzo(a)pyrene; D004958:Estradiol; D000077584:2-Methoxyestradiol; C014036:4-hydroxyestradiol; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1