4-hydroxyestradiol and Lung-Neoplasms

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.

Topics: 2-Methoxyestradiol; Adenocarcinoma; Adenocarcinoma of Lung; Animals; Aryl Hydrocarbon Hydroxylases; Benzo(a)pyrene; Cell Line, Tumor; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1B1; Estradiol; Estrogen Receptor alpha; Estrogens; Estrogens, Catechol; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mice; Mice, Nude; Ovariectomy; Up-Regulation; Xenograft Model Antitumor Assays

Lung cancer is the leading cause of cancer deaths in the United States, surpassing breast cancer as the primary cause of cancer-related mortality in women. The goal of the present study was to identify early molecular changes in the lung induced by exposure to tobacco smoke and thus identify potential targets for chemoprevention. Female A/J mice were exposed to either tobacco smoke or HEPA-filtered air via a whole-body exposure chamber (6 h/d, 5 d/wk for 3, 8, and 20 weeks). Gene expression profiles of lung tissue from control and smoke-exposed animals were established using a 15K cDNA microarray. Cytochrome P450 1b1, a phase I enzyme involved in both the metabolism of xenobiotics and the 4-hydroxylation of 17beta-estradiol (E(2)), was modulated to the greatest extent following smoke exposure. A panel of 10 genes were found to be differentially expressed in control and smoke-exposed lung tissues at 3, 8, and 20 weeks (P < 0.001). The interaction network of these differentially expressed genes revealed new pathways modulated by short-term smoke exposure, including estrogen metabolism. In addition, E(2) was detected within murine lung tissue by gas chromatography-coupled mass spectrometry and immunohistochemistry. Identification of the early molecular events that contribute to lung tumor formation is anticipated to lead to the development of promising targeted chemopreventive therapies. In conclusion, the presence of E(2) within lung tissue when combined with the modulation of cytochrome P450 1b1 and other estrogen metabolism genes by tobacco smoke provides novel insight into a possible role for estrogens in lung cancer.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Atmosphere Exposure Chambers; Biomarkers; Cryptochromes; Cytochrome P-450 CYP1B1; Enzyme Induction; Estradiol; Estrogens; Estrogens, Catechol; Female; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Humans; Lung; Lung Neoplasms; Mice; Mice, Inbred A; Microsomes; Neoplasms, Hormone-Dependent; Oligonucleotide Array Sequence Analysis; Random Allocation; RNA, Messenger; Smoking; Time Factors; Tobacco Smoke Pollution

This perspective on Meireles et al. (beginning on p. 707 in this issue of the journal) discusses the increasing evidence for the role of female steroid hormones in lung cancer development and progression. The novel work of Meireles et al. is the first evidence for the rapid upregulation by tobacco smoke of a key cytochrome P450 gene that can metabolize estrogens such as beta-estradiol to potentially carcinogenic catechol and quinine forms, as well as the first evidence for the colocalization of beta-estradiol and estrogen receptors in murine airway epithelium. Actions of estrogens that contribute to lung carcinogenesis, especially in the presence of tobacco smoke, may involve both reactive intermediates that damage DNA and steroid hormone receptor signaling that promotes growth.

Topics: Alcohol Oxidoreductases; Animals; Aryl Hydrocarbon Hydroxylases; Cell Transformation, Neoplastic; Circadian Rhythm; Cryptochromes; Cytochrome P-450 CYP1B1; Cytochrome P-450 Enzyme System; Enzyme Induction; Estradiol; Estrogens; Estrogens, Catechol; Female; Gene Expression Regulation; Humans; Lung; Lung Neoplasms; Male; Melatonin; Mice; Neoplasms, Hormone-Dependent; RNA, Messenger; Tobacco Smoke Pollution