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 ...

A significant change of vitamin E and malondialdehyde plasma concentrations was reported in breast cancer patients. This change was unexpected because vitamin E was higher and malondialdehyde lower in cases than in controls, and the difference was more significant in young rather than older women. The first aim of this study was to determine whether these changes were associated only with breast cancer, or with hormone-related cancers, and/or cancers associated with nutritional risk factors or with all types of cancers. Measurements were performed before therapy on 269 hospital-based controls and on 146 patients with various carcinomas. Vitamin E:total cholesterol increased and malondialdehyde plasma concentration decreased with tumor size and progression, without relation to the site. The second aim was to understand the difference in the change observed between young and old breast cancer patients. These analytes were measured in 365 breast cancer patients according to three prognosis factors: pathology, tumor size and estrogen receptors. Vitamin E:total cholesterol significantly decreased with estrogen receptor amount. Malondialdehyde plasma concentration decreased with severity of pathology and tumor size. Together, these data support the association of an altered oxidant-antioxidant profile in cancer patients with tumor growth and progression.

The objective of this pilot study was to determine a way of assessing personal exposure to ozone (O3) for use in a study of O3 effects on health. Passive samplers (Passam, AG) were used to measure pollution levels in Montpellier, France. They were standardized using an O3 analyzer. Blanks and duplicates were tested to evaluate sensitivity (6.6 μg/m3) and imprecision (2 μg/m3). They were validated by comparing on-site measurements with those of the automatic UV absorption analyzers of the regional air quality network (AMPADI-LR). The correlation coefficient was r = 0.9, p < 10-3, and the regression coefficient was close to 1. The on-site measurements provided information about local pollution. Distance from NO2 sources (urban traffic) and sunlight intensity were identified as environmental determinants of O3 pollution. Residential microenvironmental concentrations and personal exposure were measured for 110 subjects. The indoor/outdoor ratio is higher than in Mexico City and higher than in Toronto in summer but comparable with that in Toronto in winter. The relationship between personal exposure and indoor home measurements is closer than that between personal exposure and outdoor home environment measurements. This is especially true for the spring and summer months, when the correlation between indoor and outdoor measurements is low (r = 0.23, p < 0.05). At the workplace, on the other hand, there is a close correlation between indoor and outdoor ozone measurements in summer (r = 0.80, p < 0.001), as there is between personal exposure and outdoor measurements (r = 0.60, p < 0.001).

The role of plasma oxidant-antioxidant status in survival after breast cancer surgery was investigated in a cohort of patients (n ‫؍‬ 363) hospitalized in Southern France between 1989 and 1992. The median follow-up was 8 years after surgery for histologically confirmed breast cancer. Plasma analyses were performed after diagnosis and before surgery and adjuvant therapy. We found an inverse relationship between plasma lipoperoxides (MDA) and tumor size at diagnosis, together with higher lipoperoxide levels in node-negative tumors than in node-positive ones (TNM). The longitudinal approach revealed an increased risk of recurrence for patients with plasma lipoperoxides in the highest tertile of the sample (RR ‫؍‬ 2.1, 95%CI 1.1-4.0). In addition, the risk of recurrence increased (RR ‫؍‬ 1.7, 95%CI 1.0 -3.0), after adjustment for the known prognostic factors (TNM), for patients with plasma lipid-adjusted vitamin E levels of over 22 mol/l. The risk of breast cancer death was twice as great for patients with plasma lipid-adjusted vitamin E levels above this value. Excesses of plasma lipoperoxides and vitamin E appear to be factors in poor prognosis for breast cancer-specific survival (OVS) and disease-free survival (DFS), respectively, independent of tumor characteristics at diagnosis. Several hypotheses are advanced to explain the possible role of plasma vitamin E as a factor in poor prognosis for survival. © 2002 Wiley-Liss, Inc. Key words: breast cancer; survival; lipoperoxides; vitamin EA previous cross-sectional study that we had conducted 1 showed a statistically significant higher plasma vitamin E level in breast cancer patients than in controls. In line with these data, another of our studies 2 had shown that lipid peroxidation measured by malondialdehyde formation was lower in patients than in controls. Moreover, it was found that plasma antioxidants and lipid peroxidation were inversely associated with tumor size. 3 These results were completed by cross-sectional studies 4,5 of other cancer sites, which also showed that the risk of tumor growth increased 3-fold in the class of cancer patients in which plasma lipoperoxides were below 0.3 mol/l.These findings suggested that the oxidant-antioxidant status of patients could influence tumor growth and proliferative activity and subsequently overall survival and risk of recurrence after surgery. This hypothesis has also been investigated in other studies of both animal 6,7 and human tumors. 8 The present longitudinal study was therefore conducted to investigate the plasma concentrations of lipoperoxides, vitamin E (an antioxidant lipophile) and glutathione peroxidase (an antioxidant enzyme) as relevant prognostic factors for risk of death or recurrence for breast cancer patients. MATERIAL AND METHODS Patients and tumor characteristicsThe present study was carried out at the Val d'Aurelle-Paul

Severity of prognosis factors in breast cancer cases was found to be associated with an increase in plasma vitamin E and a decrease in plasma malondialdehyde (peroxidability index). The first aim of this study was to determine whether this association is also present in other cancers. Measurements were taken before therapy on 129 patients with various carcinomas. Cholesterol was also investigated, as vitamin E is closely related to this analyte. Patients were classified by tumor size (T < or = 5 cm and T > 5 cm) and by invasion status, assessed by the presence of nodes and/or metastasis. The vitamin E/total cholesterol concentration ratio was higher and the cholesterol and malondialdehyde concentrations were significantly lower in the plasma of patients with large tumors or in whom nodes and/or metastasis were present, whatever the site. The multivariate analysis performed to measure the association of these analyte concentrations with tumor progression showed that the presence of nodes and/or metastases was inversely associated with a low vitamin E/total cholesterol ratio (OR, 0.5; CI, 0.3-1.1) and, directly associated with low plasma concentrations of cholesterol and malondialdehyde (OR, 3.0; CI, 1.3-6.8 and OR, 2.8; CI, 1.2-6.7 respectively). The same types of associations were identified with large tumors, but were less strong. Together these findings supported an alteration of lipid parameters related to the oxidant-antioxidant status in cancer patients. This alteration appears to be associated with tumor growth and progression in patients with various cancer sites.

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Cytochrome P450 1B1 (CYP1B1) is implicated in the activation of potentially carcinogenic xenobiotics and oestrogens. The polymorphism of the CYP1B1 gene at codon 432 (Val-->Leu) is associated with change in catalytic function. In a case-series study of breast cancer patients, we investigated the interaction between this polymorphism and environmental exposure. The women carrying the Val CYP1B1 allele and who had lived near to a waste incinerator for more than 10 years had a higher risk of breast cancer than those never exposed with the Leu/Leu genotype (odds ratio of interactions (ORi)=3.26, 95% confidence interval (CI) 1.20-8.84). Also, the Val CYP1B1 allele increased the susceptibility to breast cancer for women exposed during their life to agricultural products used in farming (ORi = 2.18, 95% CI 1.10-4.32). These xenobiotics, mainly organochlorine hydrocarbons, are known to bind to the aromatic hydrocarbon receptor (AhR), and to induce the expression of CYP1B1 enzyme. The excess risk for exposed women with a Val CYP1B1 homo/heterozygous genotype could result from a higher exposure to activated metabolites of pesticides or dioxin-like substances. Also, a higher induction of CYP1B1 enzyme by xenobiotics could increase the formation of genotoxic catechol-oestrogens among exposed women carrying the Val CYP1B1 allele. Our results suggested that the Val CYP1B1 allele increases the susceptibility to breast cancer in women exposed to waste incinerator or agricultural pollutants.

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