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Smoking out reproductive hormone actions in lung cancer.

ABSTRACT: Experimental and population-based evidence has been steadily accumulating that steroid hormones are fundamentally involved in the biology of the lung. Both estrogen and progesterone receptors are present in normal and malignant lung tissue, and the reproductive hormones that bind these receptors have a role in lung development, lung inflammation, and lung cancer. The estrogen receptor-? (ER-?) was discovered in the 1990s as a novel form of ER that is transcribed from a gene distinct from ER-?, the receptor previously isolated from breast tissue. Interestingly, ER-? is the predominate ER expressed in normal and malignant lung tissue, whereas inflammatory cells that infiltrate the lung are known to express both ER-? and ER-?. Although there is evidence from animal models for the preferential effects of ER-? in the lungs of females, human lung tumors from males often contain comparable numbers of ER-?-positive cells and male-derived lung cancer cell lines respond to estrogens. Lung tumors from both males and females also express CYP19 (aromatase), the rate-limiting enzyme in estrogen synthesis that converts testosterone to estrone and ?-estradiol. Thus, testosterone acts as a precursor for local estrogen production within lung tumors, independent of reproductive organs. This review discusses the recent literature findings about the biology of the ERs, aromatase, and the progesterone receptor in lung cancer and highlights the ongoing clinical trials and future therapeutic implications of these findings.

SUBMITTER: Siegfried JM

PROVIDER: S-EPMC3972805 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Smoking out reproductive hormone actions in lung cancer.

Siegfried Jill M JM

Molecular cancer research : MCR 20140107 1

Experimental and population-based evidence has been steadily accumulating that steroid hormones are fundamentally involved in the biology of the lung. Both estrogen and progesterone receptors are present in normal and malignant lung tissue, and the reproductive hormones that bind these receptors have a role in lung development, lung inflammation, and lung cancer. The estrogen receptor-β (ER-β) was discovered in the 1990s as a novel form of ER that is transcribed from a gene distinct from ER-α, t ...[more]

PMID: 24398390

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Project description:BACKGROUND:A low level of methylation at cg05575921 in the aryl-hydrocarbon receptor repressor (AHRR) gene is robustly associated with smoking, and some studies have observed associations between cg05575921 methylation and increased lung cancer risk and mortality. To prospectively examine whether decreased methylation at cg05575921 may identify high risk subpopulations for lung cancer screening among heavy smokers, and mortality in cases, we evaluated associations between cg05575921 methylation and lung cancer risk and mortality, by histotype, in heavy smokers. METHODS:The ?-Carotene and Retinol Efficacy Trial (CARET) included enrollees ages 45-69 with ? 20 pack-year smoking histories and/or occupational asbestos exposure. A subset of CARET participants had cg05575921 methylation available from HumanMethylationEPIC assays of blood collected on average 4.3?years prior to lung cancer diagnosis in cases. Cg05575921 methylation ?-values were treated continuously for a 10% methylation decrease and as quintiles, where quintile 1 (Q1, referent) represents high methylation and Q5, low methylation. We used conditional logistic regression models to examine lung cancer risk overall and by histotype in a nested case-control study including 316 lung cancer cases (diagnosed through 2005) and 316 lung cancer-free controls matched on age (±5?years), sex, race/ethnicity, enrollment year, current/former smoking, asbestos exposure, and follow-up time. Mortality analyses included 372 lung cancer cases diagnosed between 1985 and 2013 with available methylation data. We used Cox proportional hazards models to examine mortality overall and by histotype. RESULTS:Decreased cg05575921 methylation was strongly associated with smoking, even in our population of heavy smokers. We did not observe associations between decreased pre-diagnosis cg05575921 methylation and increased lung cancer risk, overall or by histotype. We observed linear increasing trends for lung cancer-specific mortality across decreasing cg05575921 methylation quintiles for adenocarcinoma and small cell carcinoma (P-trends?=?0.01 and 0.04, respectively). CONCLUSIONS:In our study of heavy smokers, decreased cg05575921 methylation was strongly associated with smoking but not increased lung cancer risk. The observed association between cg05575921 methylation and increased mortality in adenocarcinoma and small cell histotypes requires further examination. Our results do not support using decreased cg05575921 methylation as a biomarker for lung cancer screening risk stratification.

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Smoking out reproductive hormone actions in lung cancer.

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Smoking out reproductive hormone actions in lung cancer.

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