| Abstract: |
We performed a discovery genome-wide association study to identify genetic factors associated with variation in plasma estradiol (E2) concentrations using DNA from 772 postmenopausal women with estrogen receptor (ER)-positive breast cancer prior to the initiation of aromatase inhibitor therapy. Association analyses showed that the single nucleotide polymorphisms (SNP) (rs1864729) with the lowest P value (P = 3.49E-08), mapped to chromosome 8 near TSPYL5. We also identified 17 imputed SNPs in or near TSPYL5 with P values <; 5E-08, one of which, rs2583506, created a functional estrogen response element. We then used a panel of lymphoblastoid cell lines (LCLs) stably transfected with ERβ with known genome-wide SNP genotypes to demonstrate that TSPYL5 expression increased after E2 exposure of cells heterozygous for variant TSPYL5 SNP genotypes, but not in those homozygous for wild-type alleles. TSPYL5 knockdown decreased, and overexpression increased aromatase (CYP19A1) expression in MCF-7 cells, LCLs, and adipocytes through the skin/adipose (I.4) promoter. Chromatin immunoprecipitation assay showed that TSPYL5 bound to the CYP19A1 I.4 promoter. A putative TSPYL5 binding motif was identified in 43 genes, and TSPYL5 appeared to function as a transcription factor for most of those genes. In summary, genome-wide significant SNPs in TSPYL5 were associated with elevated plasma E2 in postmenopausal breast cancer patients. SNP rs2583506 created a functional estrogen response element, and LCLs with variant SNP genotypes displayed increased E2-dependent TSPYL5 expression. TSPYL5 induced CYP19A1 expression and that of many other genes. These studies have revealed a novel mechanism for regulating aromatase expression and plasma E2 concentrations in postmenopausal women with ER(+) breast cancer. © 2013 by The Endocrine Society. |
| Keywords: |
adult; aged; unclassified drug; human cell; major clinical study; promoter region; single nucleotide polymorphism; polymorphism, single nucleotide; allele; gene; estrogen responsive element; gene expression; protein binding; genetic association; genetic variability; genotype; genome-wide association study; transcription factor; breast neoplasms; heterozygote; chromosomes, human, pair 8; wild type; nuclear proteins; gene expression regulation, neoplastic; molecular sequence data; genetic transfection; rna, messenger; chromatin immunoprecipitation; promoter regions, genetic; homozygote; base sequence; chromosome 8; postmenopause; estradiol; mcf-7 cells; lymphoblastoid cell line; aromatase; estradiol blood level; gene expression regulation, enzymologic; adipocyte; genetic association studies; estrogen receptor positive breast cancer; nucleotide motifs; transcription factor tspyl5
|
