Cyp17, Urinary Sex Steroid Levels and Breast Cancer Risk in Postmenopausal Women

Abstract

Endogenous sex hormones play an important role in the etiology of breast cancer. Polymorphisms in genes encoding for enzymes involved in steroidogenesis may therefore play a role in breast cancer risk. Cytochrome P450c17a (Cyp17) functions at key branch points in human steroidogenesis. A T! !C transition (A1 and A2 allele) in the 5V untranslated region may be associated with increased expression of Cyp17. Using a case-cohort design, we studied the effects of the A2 allele on endogenous sex hormone levels and breast cancer risk within a large population-based cohort (n = 9,349) in the Netherlands (the DOM-cohort). Cyp17 genotype was determined in 335 incident postmenopausal breast cancer cases, which occurred after follow-up (median time to follow-up, 19 years) of the entire cohort, and in a random sample of 373 women (subcohort). Concentrations of estrone (E 1 ), estradiol (E 2 ), testosterone, 5a-androstane-3a, 17B-diol (3aD), and creatinine were measured in first-morning urine samples. Only among women with body mass index (BMI) < 25 kg/m 2 was the A2A2 genotype associated with higher levels of E 1 , E 2 , and 3aD compared with a group of women with either the A1A1 or the A1A2 genotype (e.g., geometric means of E 1 in ng/ mg creatinine : A2A2, 2.23; A1A1/A1A2, 1.47; P = 0.03). Adjusted breast cancer rate ratios for women with the A1A2 or A2A2 genotype compared with women with the A1A1 genotype were 0.96 (0.68-1.37) and 0.80 (0.47-1.35), respectively. These results did not differ between women with low and high BMI.In conclusion, this paper shows that women with low BMI and the A2A2 genotype had higher endogenous sex steroid levels compared with women with the A1A1 genotype. However, these increased sex steroid levels are not translated into an increased breast cancer risk in these women. (Cancer Epidemiol Biomarkers Prev 2005;14(4): 815 -20)

Association of genetic polymorphisms of ER-α and the estradiol-synthesizing enzyme genes CYP17 and CYP19 with breast cancer risk in Chinese women

“…We thus examined associations between CYP17 genotypes and hormone-related risk factors, and we found that the CYP17 C variant genotypes were associated with breast cancer among women with pregnancy times [2, or with high BMI (C23 kg/m 2 ), or with breastfeeding \12 months. Interestingly, a report from a similar size of study showed that women with low BMI and the A2A2 (CC) genotype had higher endogenous sex steroid levels, but this did not translate into an increased breast cancer risk [23], further underscoring the multi-factorial effect in determination of breast cancer risk. Aromatase is the enzyme responsible for catalyzing the final step of conversion of androgens into estrogens.…”

Factors influencing the association between CYP17 T34C polymorphism and the risk of breast cancer: meta-regression and subgroup analysis

“…Taken together, these findings may contribute to the increased risk in women with C allele and early age at menarche. Finally, CYP17 C carriers in post-menopausal women were thought to be positively related to high BMI [30], thereby having high hormone levels [63]. Under this premise, they may be more susceptible to breast cancer.…”

Variants in hormone biosynthesis genes and risk of endometrial cancer

“…In addition, there is no evidence of association of genotype with serum levels of androgens, the precursors of estrogens (Figure 1). Higher levels of estrogens in women with the C allele have been reported in saliva [27], urine [28], and follicular fluid [29]. The association of the variant with higher levels of estrogen found in some studies would lead to the hypothesis that it would increase risk of endometrial cancer, in contrast to the reductions in risk noted in this and some other studies.…”