Abstract P5-13-07: Genetic polymorphism of estrogen metabolizing enzyme CYP17A1 rs743572 impacts on serum testosterone level in Japanese premenopausal women

Abstract

Abstract The incidence of breast cancer in Japanese women has doubled in all age groups over the past two decades. We recently demonstrated that this marked increase is mostly due to an increase in the estrogen receptor (ER)-positive subtype, and we created risk prediction models for ER-positive breast cancer in both pre- and post- menopausal women using genetic factors (single nucleotide polymorphism (SNP)), environmental risk factors, serum hormones and growth factors by logistic regression analysis. Serum level of testosterone, which is the precursor of estradiol in estradiol synthesis, was found to be a risk predictor in both pre- and post- menopausal women. On the other hand, it has been reported that some SNPs, including those of estrogen-related genes such as ESR1 and CYP17A1, are correlated with breast cancer risk by genome-wide association studies. To acquire some insights into this mechanism, we analyzed genetic factors (14 SNPs), serum hormones and growth factors (estradiol, testosterone, prolactin, insulin-like growth factor 1 (IGF1) and IGF binding protein 3 (IGFBP3)) in 913 women with breast cancer and 278 disease-free controls for correlation between them. Serum testosterone and prolactin levels were significantly higher in ER-positive breast cancer patients than in disease-free controls in both pre- (p<0.0001, p<0.0001) and post- (p<0.0001, p = 0.007) menopausal women, and serum estradiol level was significantly higher in ER-positive breast cancer patients than in disease-free controls only in premenopausal women (p = 0.0005). There were significant differences in serum hormone levels among the women with each SNP genotype (homozygotes of major allele, heterozygotes and homozygotes of minor allele), including testosterone among rs743572 genotype (p = 0.014), estradiol among rs827421 genotype (p = 0.016), IGF-1 among rs6905370 genotype (p = 0.032), and prolactin among rs1042522 genotype (p = 0.035) in premenopausal women, as well as estradiol among rs3803662 genotype (p = 0.027) and IGFBP3 among rs6905370 genotype (p = 0.036) in postmenopausal women. In particular, serum testosterone level was significantly different among the rs743572, which is one of the enzymes that convert testosterone to estradiol, of genotypes (AA: 0.308 +/- 0.180 ng/ml, AG: 0.319 +/- 0.193 ng/ml and GG: 0.380 +/- 0.187 ng/ml, p = 0.014). On the other hand, the rs743572 heterozygotes of CYP17A1 have been reported to have increased breast cancer risk than homozygotes of both the major allele and minor allele in premenopausal women. Further studies are required to clarify this mechanism. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-07.