Role of Estradiol Metabolism and CYP1A1 Polymorphisms in Breast Cancer Risk

Abstract

The endogenous metabolism of estrogens is primarily oxidative and involves hydroxylation of the steroid at either C2 (2-OHE1) or C16 (16-OHE1). While the 2-OHE1 metabolites are essentially devoid of peripheral biological activity, 16-OHE1 is an estrogen agonist. There is evidence of an association between the 2-OHE1/16-OHE1 metabolites ratio and breast cancer risk. The CYP1A1 gene may play a role in the 2-hydroxylation (2-OH) of estradiol. African-American women with the wild-type CYP1A1 gene showed a significant increase in the 2-OHE1/16-OHE1 ratio, from 1.35 +/- 0.56 at baseline to 2.39 +/- 0.98 (p = 0.006) after 5 days of treatment with indole-3-carbinol (400 mg/day), a 2-OHE1 inducer. Women with the Msp1 polymorphism showed no significant increase, (0.37% +/- 0.17%). In a case-control study involving 57 women with breast cancer and 312 female controls, the frequency of the homozygous Msp1 polymorphism was 4.2% in African-American controls and 16% in African-American breast cancer cases. The odds ratio of breast cancer with the Msp1 homozygous variant was 8.4 (95% confidence interval: 1.7-41.7). This association was not observed in Caucasian women. The other CYP1A1 polymorphisms were not associated with breast cancer. The CYP1A1 Msp1 polymorphism may be a marker of altered estradiol metabolism and of increased susceptibility to estrogen-related breast cancer in African-Americans.

Cytochrome P450 1A1 (CYP1A1) T3801C and A2455G polymorphisms in breast cancer risk: a meta-analysis

“…Among all the eligible articles, four described the T3801C polymorphism, two focused on A2455G, and nine articles investigated both T3801C and A2455G. In these latter nine articles, the genotyping data for T3801C deviated from HWE in Chacko et al (2005), Taioli et al (1999) and Bailey et al (1998), while the genotyping data for A2455G matched HWE in these three studies; the genotyping data for A2455G in Hefler et al (2004) deviated from HWE, while the genotyping data for T3801C matched HWE in this paper. We extracted the available data, rejected datasets where HWE was doubtful.…”

“…In the analysis of T3801C in Table 2 Distribution of T3801C and A2455G genotype and allele among breast cancer cases and controls included in the meta-analysis Africans or African-Americans, between-study heterogeneity still existed in subgroups. Analyzing the high heterogeneity for T3801C, we found that when Shen et al (2006) was excluded, the betweenstudy heterogeneity in east-Asians was decreased significantly (from P = 0.0005 to P = 0.04); when Taioli et al (1999) was removed, the between-study heterogeneity in Africans no longer existed (from P = 0.03 to P = 0.26). If both these studies were eliminated, no between-study heterogeneity was found in the worldwide population (from P = 0.001 to P = 0.28).…”

“…It is possible that the selected populations in these two articles were from separate areas in Shanghai, but further studies are needed to clarify the reason for the difference. Taioli et al (1999) contained two studies based on two United States populations (African-American and White). However, only the data on African-Americans contribute to between-study heterogeneity.…”

“…Based on the search criteria, 17 articles (Ambrosone et al 1995;Bailey et al 1998;Basham et al 2001;Boyapati et al 2005;Chacko et al 2005;Hefler et al 2004;Huang et al 1999aHuang et al , 1999bKrajinovic et al 2001;Le Marchand et al 2005;Li et al 2004;Miyoshi et al 2002;Okobia et al 2005;Shen et al 2006;Singh et al 2006;Taioli et al 1995Taioli et al , 1999 were identified by reviewing 66 papers. Two of these articles were finally excluded as the studies of Taioli et al (1995) and Huang et al (1999a) were replaced by their later reports (Taioli et al 1999;Huang et al 1999b, respectively).…”

“…Two of these articles were finally excluded as the studies of Taioli et al (1995) and Huang et al (1999a) were replaced by their later reports (Taioli et al 1999;Huang et al 1999b, respectively). Three articles (Li et al 2004;Taioli et al 1999;Bailey et al 1998) provided data on two ethnicities: African-American and Caucasians. Each subpopulation in these articles was treated as a separate study in our metaanalysis.…”