Results of epidemiological studies suggest that, after one controls for the number of cigarettes smoked, women have a three times higher risk of getting lung cancer than men. Although the mechanism(s) explaining this gender-dependent difference in lung cancer risk is not known, it is thought that endocrine factors may play an important role. Normal human bronchial epithelial cells contain estrogen receptors and synthesize 17β-estradiol (E(2)) and estrone (E(1)), which can undergo further metabolism into the catechol estrogens, 4-hydroxyestradiol (4-OHE(2)) and 4-hydroxyestrone (4-OHE(1)), respectively. Catechol estrogens are formed from E(2) by the actions of cytochrome p450 1B1 (CYP1B1). CYP1B1 is present in normal human bronchial epithelial) cells, and its activity is increased by cigarette smoking. Both 4-OHE(1) and 4-OHE(2) are mutagenic and carcinogenic and may exert their biological effects by inducing DNA adducts in cancer-related genes, including the tumor suppressor gene p53 and the proto-oncogene K-ras. Women with lung cancer have a different p53 mutational spectrum and a higher frequency of K-ras mutations than do men with lung cancer. Both clinical and basic research studies support the hypothesis that E(2) and cigarette smoking are cofactors in lung carcinogenesis in women. More specifically, cigarette smoke stimulates metabolism of E(2) into the genotoxic metabolites, 4-OHE(1) and 4-OHE(2,) which interact with DNA in cancer-related genes, including the tumor suppressor gene, p53, and the proto-oncogene K-ras, two genes frequently mutated in patients with lung cancer. E(2) may stimulate cellular proliferation and enhance tumor growth.
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