ER alpha phenotype, estrogen level, and benzo[a]pyrene exposure modulate tumor growth and metabolism of lung adenocarcinoma cells

作者：Lin Susana; Lin Chun Ju; Hsieh Dennis P H; Li Lih Ann^*

来源：Lung Cancer, 2012, 75(3): 285-292.

DOI：10.1016/j.lungcan.2011.08.010

• Lung adenocarcinoma
• ER alpha
• Tumor growth
• Benzo[a]pyrene
• Estrogen metabolism
• Gene regulation

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 ER alpha 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 ER alpha expression were transplanted into female nude mice. Results showed that estrogen promoted tumor growth of ER alpha(+) lung adenocarcinoma cells but inhibited that of ER alpha(-) lung adenocarcinoma cells. Endocrine disruptor benzo[a]pyrene stimulated ER alpha(-) tumor growth dose dependently. Either of ovariectomy and ER alpha expression abolished the tumor growth-promoting effect of benzo[a]pyrene. The high CYP1B1/CYP1A1 and low COMT/CYP1B1 expression ratios detected in ER alpha(+) 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 ER alpha(-) tumors. Inhibition of estrogen on ER alpha(-) 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 ER alpha(-) tumor cells, probably switching estrogen metabolism to 4-hydroxyestradiol formation and removing the inhibition of 2-methoxyestradiol on ER alpha(-) tumors. ER alpha 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 ER alpha(+) lung adenocarcinoma growth by up-regulating cancer-related ER alpha target gene expression.

• 出版日期2012-3