title: 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.
authors.affiliation: Section of Oncology, Department of Clinical Science, University of Bergen, Norway; Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Anne Hege
authors.initials: AH
authors.lastname: Straume
authors.affiliation: Section of Oncology, Department of Clinical Science, University of Bergen, Norway; Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Stian
authors.initials: S
authors.lastname: Knappskog
authors.affiliation: Section of Oncology, Department of Clinical Science, University of Bergen, Norway; Department of Oncology, Haukeland University Hospital, Bergen, Norway. Electronic address: per.lonning@helse-bergen.no.
authors.forename: Per Eystein
authors.initials: PE
authors.lastname: Lønning
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D004958:Estradiol / Q000378:metabolism*; D004960:Estradiol Dehydrogenases / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011863:Radioimmunoassay; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human
keywords: 17β-HSD2; 17β-HSD7; Breast cancer; Gene expression; Postmenopausal oestrogen synthesis; Single nucleotide polymorphisms