Effects of SNP variants in the 17β-HSD2 and 17β-HSD7 genes and 17β-HSD7 copy number on gene transcript and estradiol levels in breast cancer tissue

Abstract

Breast cancers reveal elevated E2 levels compared to plasma and normal breast tissue. Previously, we reported intra-tumour E2 to be negatively correlated to transcription levels of 17β-HSD2 but positively correlated to 17β-HSD7. Here, we explored these mechanisms further by analysing the same breast tumours for 17β-HSD2 and -7 SNPs, as well as 17β-HSD7 gene copy number. Among the SNPs detected, we found the 17β-HSD2 rs4445895_T allele to be associated with lower intra-tumour mRNA (p = 0.039) and an elevated intra-tumour E2 level (p = 0.006). In contrast, we found the 17β-HSD7 rs1704754_C allele to be associated with elevated mRNA (p = 0.050) but not to E2 levels in breast tumour tissue. Surprisingly, 17β-HSD7 – gene copy number was elevated in 19 out of 46 breast tumours examined. Elevated copy number was associated with an increased mRNA expression level (p = 0.013) and elevated tumour E2 (p = 0.025). Interestingly, elevated 17β-HSD7 – gene copy number was associated with increased expression not only of 17β-HSD7, but the 17β-HSD7_II pseudogene as well (p = 0.019). Expression level of 17β-HSD7 and its pseudogene was significantly correlated both in tumour tissue (rs = 0.457, p = 0.001) and in normal tissue (rs = 0.453, p = 0.002). While in vitro transfection experiments revealed no direct impact of 17β-HSD7 expression on pseudogene level, the fact that 17β-HSD7 and 17β-HSD7_II share a 95.6% sequence identity suggests the two transcripts may be subject to common regulatory mechanisms. In conclusion, genetic variants of 17β-HSD2 and 17β-HSD7 may affect intra-tumour gene expression as well as breast cancer E2 levels in postmenopausal women.