Polymorphism of hormone synthesis and metabolizing genes and breast cancer risk: A multigenic case-control study

Abstract

Endogenous and exogenous hormones influence breast cancer risk including estrogen biosynthesis pathway, vitamin D receptor pathway, and the androgen receptor pathway. Genes involved in these pathways are CYP17, which encodes an enzyme involved in estradiol and testosterone synthesis, androgen receptor (AR), which binds testosterone and DHT and regulates breast cell growth and the vitamin D receptor (VDR), which binds vitamin D and down-regulates breast growth.The current study was proposed to determine whether polymorphisms in the CAG repeat in exon 1 of AR, MspAI T > C substitution of CYP17, and ApaI, 7aqI, poly-A repeat in the VDR gene contribute to breast cancer risk. Logistic regression models were used to evaluate individual and joint contributions of genotypes to breast cancer risk.Seventy (70) breast cancer patients and eighty healthy women (80) were recruited for the study. PCR based RFLP and fragment analysis assays were used to determine genotypes of hormone metabolizing genes. Considering CYP17 A2 allele, VDR Poly-(A) L, and AR ≥ 20 CAG repeats as high risk alleles, a multigenic model of breast cancer susceptibility was developed to identify women who carry a combination of alleles to put them at relatively higher risk to develop breast cancer. All the high-risk genotypes were positively associated with risk. The risk among women carrying three high-risk alleles was OR:4.68 [95% confidence interval (CI), 0.77-28.0; p for trend = 0.10] compared with those who carried none. The conditional logistic regression analysis revealed that the heterozygous TC genotype for CYP17 and AR1AR2 of AR, imparted significantly fourfold risk for the breast cancer risk, in comparison to the referent genotype TT and AR1AR1 [adjusted ORs:3.705(1.236,11.106), p = 0.019] and [4.391(1.324,14.557), p = 0.016], respectively. Gene X Gene interaction showed that the combinations TC*AA, TC*Aa, TC*aa and CC*Aa imparted significantly four to fifteen fold more risk for the breast cancer [(4.377 (1.159, 16.520), p = 0.029); 4.041(1.092, 14.956), p = 0.036); (15.071(0.975, 232.81), p = 0.052); (4.151(1.053, 16.371), p = 0.042), respectively)]. Genes involved in hormone synthesis and metabolizing pathway may play a role in breast cancer development as supported by the multigenic model of breast cancer susceptibility.