Smoking out reproductive hormone actions in lung cancer.

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, the receptor previously isolated from breast tissue. Interestingly, ER-β is the predominate ER expressed in normal and malignant lung tissue, whereas inflammatory cells that infiltrate the lung are known to express both ER-α and ER-β. Although there is evidence from animal models for the preferential effects of ER-β in the lungs of females, human lung tumors from males often contain comparable numbers of ER-β-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 β-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.