Interactions between genetic polymorphism of cytochrome P450‐1B1, sulfotransferase 1A1, catechol‐o‐methyltransferase and tobacco exposure in breast cancer risk

Abstract

Genetic polymorphisms of enzymes involved in the metabolism of xenobiotics and estrogens might play a role in breast carcinogenesis related to environmental exposures. In a case-only study on 282 women with breast cancer, we studied the interaction effects (ORi) between smoking habits and the gene polymorphisms of Cytochrome P450 1B1 (Val432Leu CYP1B1), Phenol-sulfotransferase 1A1 (Arg213His SULT1A1) and Catechol-O-methyltransferase (Val158Met COMT). The smokers carrying the Val CYP1B1 allele associated with a high hydroxylation activity had a higher risk of breast cancer than never smokers with the Leu/Leu genotype (ORi‫,23.2؍‬ 95%CI: 1.00 -5.38). Also, the smokers carrying the His SULT1A1 allele associated with a low sulfation activity had a 2-fold excess risk compared to never smokers carrying Arg/Arg SULT1A1 common genotype (ORi‫؍‬ 2.55, 95%CI: 1.21-5.36). The His SULT1A1 allele increased the risk only in premenopausal patients. The Met COMT allele with a lower methylation activity than Val COMT did not modify the risk among smokers. The excess risk due to joint effect could result from a higher exposure to activated tobacco-compounds for women homo/ heterozygous for the Val CYP1B1 allele. Also, a lower sulfation of the tobacco carcinogens among women with His SULT1A1 could increase exposure to genotoxic compounds. Alternatively, the Val CYP1B1 or His SULT1A1 allele with modified ability to metabolize estrogens could increase the level of genotoxic catechol estrogen (i.e., 4-hydroxy-estradiol) among smokers. Our study showed that gene polymorphisms of CYP1B1 and SULT1A1 induce an individual susceptibility to breast cancer among current smokers. © 2003 Wiley-Liss, Inc. Key words: CYP1B1; SULT1A1; COMT; gene polymorphism; tobacco; breast cancerLittle is known about genotoxic factors in breast cancer development, whereas promotional factors related to sexual hormones or growth factors are well identified. 1-3 Endogenous compounds such as catechol estrogens are believed to be genotoxic for mammary epithelium and thus are suspected to play a role in breast carcinogenesis. 4 -7 Certain environmental factors have long been suspected of being genotoxic agents. 8 So far, ionizing radiation is the only known exogenous genotoxic risk factor for breast cancer. Tobacco smoke contain a variety of procarcinogens such as polycyclic aromatic hydrocarbons and heterocyclic aromatic amines, 9 which can be metabolized and activated by mammary cells and may be involved in breast carcinogenesis among tobacco-exposed women. 10 -12 However, the relationship between tobacco smoke and breast carcinogenesis is complex. 13,14 It has been suggested that particular mainstream cigarette compounds display anti-estrogenic effects. 15,16 Some studies on passive smoking have shown a tendency towards an increased breast cancer risk, 17-20 although this was not observed in a prospective study. 21 Most environmental carcinogens are metabolically activated and detoxified by polymorphic enzymes. Some of these enzymes are also involved in estrogen ...

Pharmacogenetics and Regulation of Human CytochromeP450 1B1: Implications in Hormone-Mediated Tumor Metabolism and a Novel Target for Therapeutic Intervention

“…The inconsistency between these studies may show the variability of other genetic and environmental factors linked to CYP1B1 expression and metabolism during breast carcinogenesis in different populations. These could include but are certainly not limited to body mass index (129), catechol-O-methyltransferase status (131), CYP1A1 status (43), ER status (124), having undergone menopause, and exposure to environmental carcinogens (137).…”

“…Such studies have found that smoking confers a further increase in breast cancer risk in individuals with the CYP1B1*3/*3 genotype (137). A prevailing hypothesis is that CYP1B1 is transcriptionally induced by polyaromatic hydrocarbons and other aromatic hydrocarbons (major constituents of cigarette smoke) resulting in increased levels of CYP1B1.…”

“…A prevailing hypothesis is that CYP1B1 is transcriptionally induced by polyaromatic hydrocarbons and other aromatic hydrocarbons (major constituents of cigarette smoke) resulting in increased levels of CYP1B1. Those individuals that carry the hyperactive CYP1B1*3/*3 genotype are more likely to metabolize a polycyclic aromatic hydrocarbons and endogenous procarcinogens into toxic metabolites resulting in a further increase in exposure to carcinogens compared with nonsmokers (137). As is the case for prostate cancer, DNA methylation may be an important determinant of CYP1B1 expression in breast and has been shown to predict the response to tamoxifen therapy (41).…”

Genetic Polymorphisms of SULT1A1 and SULT1E1 and the Risk and Survival of Breast Cancer

“…Some rather small previous studies (103-444 cases) involving different ethnic study populations that have explored the potential association between the SULT1A1 c.779G>A polymorphism and breast cancer risk have shown inconsistent results (6)(7)(8)(9). A number of studies with conflicting outcomes have also been conducted on SULT1A1 c.779G>A polymorphism and cancers of lung, colon, prostate, bladder, esophagus, and urinary tract (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

Role of Polymorphic Human Cytochrome P450 Enzymes in Estrone Oxidation

“…Genetic polymorphisms that influence expression and activity have been identified for all five of these enzymes. However, only genetic polymorphisms in CYP1A1 and CYP1B1 have been studied in association with breast cancer risk to date (53)(54)(55)(56)(57)(58)(59)(60)(61), with conflicting results.…”