Study on serum organochlorines pesticides (DDTs) level, CYP1A1 genetic polymorphism and risk of breast cancer: a case control study
To study the potential effect of gene-environment interaction between CYP1A1 and serum dichlorodiphenyldichloroethane (DDT) levels on the risk of breast cancer in women, in China.
A case-control study was conducted. From Dec. 2003 to Sep. 2004, 104 women with histologically confirmed breast cancers and 154 noncancerous controls from a community were enrolled in this study. Risk factors information of breast cancer was investigated by a questionnaire. Serum p, p'-dichlorodiphenyldichloroethane (p, p'-DDT) and 1, 1-dichloro-2, 2-bis (p-chlorophenyl) ethylene (p, p'-DDE) levels were tested by GC-ECD. CYP1A1 m2 gene type was tested by allele special-PCR method.
Serum DDT levels of case and control were (36.90 +/- 79.41) ng/ml and (50.60 +/- 150.70) ng/ml respectively. Serum 1, 1-dichloro-2, 2-bis (p-chlorophenyl) ethylene (p, p'-DDE) levels of case and control were (7.43 +/- 11.10) ng/ml and (8.96 +/- 11.30) ng/ml respectively. No statistically significant differences were found between the two groups with geometric mean t-test (P > 0.05). Compared with women who had homozygous wild-type CYP1A1 m2 genotype, significantly increased risks of breast cancer were found for women with the CYP1A1 m2 homozygous variant genotype [odds ratio (OR) = 2.61, 95% confidence interval (CI): 1.00 - 6.80]. Among premenopausal women, compared with women with homozygous wild-type of CYP1A1 genotype (Ile/Ile) and low serum DDT level (DDT serum level < or = 42.93 ng/ml), women with at least one variant allele of CYP1A1 m2 genotype and high serum DDT level (DDT serum level > or = 42.93 ng/ml) had higher risk of breast cancer (OR = 4.35, 95% CI: 1.140 - 16.950).
CYP1A1 m2 genetic polymorphism was associated with increased risk of female breast cancer while DDT exposure might have increased the risk of breast cancer among premenopausal women with CYP1A1 m2 variant genotype.
Available from: Weiqin Li
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ABSTRACT: Previous studies suggested that smoking and passive smoking could increase the risk of breast cancer, but the results were inconsistent, especially for Chinese females. Thus, we systematically searched cohort and case-control studies investigating the associations of active and passive smoking with breast cancer risk among Chinese females in four English databases (Pubmed, Embase, ScienceDirect, and Wiley) and three Chinese databases (CNKI, WanFang, and VIP). Fifty-one articles (3 cohort studies and 48 case-control studies) covering 17 provinces of China were finally included in this systematic review. Among Chinese females, there was significant association between passive smoking and this risk of breast cancer [odds ratio (OR): 1.62, 95% confidence interval (CI): 1.39-1.85; I2 = 75.8%, P < 0.001; n = 26] but no significant association between active smoking and the risk of breast cancer (OR: 1.04, 95% CI: 0.89-1.20; I2 = 13.9%, P = 0.248; n = 31). The OR of exposure to husband's smoking and to smoke in the workplace was 1.27 (95% CI: 1.07-1.50) and 1.66 (95% CI: 1.07-2.59), respectively. The OR of light and heavy passive smoking was 1.11 and 1.41, respectively, for women exposed to their husband's smoke (< 20 and ≥ 20 cigarettes per day), and 1.07 and 1.87, respectively, for those exposed to smoke in the workplace (<300 and ≥300 min of exposure per day). These results imply that passive smoking is associated with an increased risk of breast cancer, and the risk seems to increase as the level of passive exposure to smoke increases among Chinese females. Women with passive exposure to smoke in the workplace have a higher risk of breast cancer than those exposed to their husband's smoking.
Available from: mcr.aacrjournals.org
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ABSTRACT: Therapy resistance represents a major clinical challenge in disseminated prostate cancer for which only palliative treatment is available. One phenotype of therapy-resistant tumors is the expression of somatic, gain-of-function mutations of the androgen receptor (AR). Such mutant receptors can use noncanonical endogenous ligands (e.g., estrogen) as agonists, thereby promoting recurrent tumor formation. Additionally, selected AR mutants are sensitized to the estrogenic endocrine-disrupting compound (EDC) bisphenol A, present in the environment. Herein, screening of additional EDCs revealed that multiple tumor-derived AR mutants (including T877A, H874Y, L701H, and V715M) are sensitized to activation by the pesticide 2,2-bis(4-chlorophenyl)-1,1-dichloroethylene (DDE), thus indicating that this agent may impinge on AR signaling in cancer cells. Further investigation showed that DDE induced mutant AR recruitment to the prostate-specific antigen regulatory region, concomitant with an enhancement of target gene expression, and androgen-independent proliferation. By contrast, neither AR activation nor altered cellular proliferation was observed in cells expressing wild-type AR. Activation of signal transduction pathways was also observed based on rapid phosphorylation of mitogen-activated protein kinase (MAPK) and vasodilator-stimulated phosphoprotein, although only MAPK activation was associated with DDE-induced cellular proliferation. Functional analyses showed that both mutant AR and MAPK pathways contribute to the proliferative action of DDE, as evidenced through selective abrogation of each pathway. Together, these data show that exposure to environmentally relevant doses of EDCs can promote androgen-independent cellular proliferation in tumor cells expressing mutant AR and that DDE uses both mutant AR and MAPK pathways to exert its mitogenic activity.
Available from: Theodoros N Sergentanis
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ABSTRACT: Cytochrome P450s are enzymes which catalyze Phase-I metabolism reactions; cytochrome P450 1A1 (CYP1A1) is a member of the CYP1 family and participates in the metabolism of a vast number of xenobiotics, as well as endogenous substrates. Four single nucleotide polymorphisms in CYP1A1 have been studied concerning their potential implication in terms of breast cancer risk: T3801C, T3205C, A2455G (Ile462Val), and C2453A (Thr461Asp); controversy exists regarding their role. This meta-analysis aims to examine whether the four aforementioned polymorphisms are associated with breast cancer risk. Separate analyses were performed on Caucasian, Chinese, and African populations, as well as on premenopausal and postmenopausal women. Eligible articles were identified by a search of MEDLINE bibliographical database for the period up to October 2009. Concerning T3801C, 32 studies were eligible (11,909 cases and 16,179 controls), 29 studies (12,257 cases and 20,379 controls) were eligible for A2455G, 11 studies (7,189 cases and 8,491 controls) were eligible for C2453A, and eight studies were eligible for T3205C (1,378 cases and 1,642 controls). Pooled odds ratios (OR) were appropriately derived from fixed- or random-effect models. Sensitivity analysis excluding studies whose genotype frequencies in controls significantly deviated from Hardy-Weinberg equilibrium was performed. Homozygous subjects of Caucasian origin carrying the A2455G G allele exhibited elevated breast cancer risk (pooled OR = 2.185, 95% CI 1.253-3.808, fixed effects), whereas heterozygous carriers did not (pooled OR = 1.062, 95% CI 0.852-1.323, random effects). A2455G polymorphism status was not associated with breast cancer risk in Chinese subjects or specifically in premenopausal/postmenopausal women. T3801C, T3205C, and C2453A status were not associated with breast cancer risk at any analysis. In conclusion, this meta-analysis points to the A2455G G allele as a risk factor for breast cancer among Caucasian subjects. On the contrary, T3801C, T3205C, and C2453A status does not seem capable of modifying breast cancer risk.
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