TSPYl5 SNPs: Association with plasma estradiol concentrations and aromatase expression

Mohan Liu, James N. Ingle, Brooke L. Fridley, Aman U. Buzdar, Mark E. Robson, Michiaki Kubo, Liewei Wang, Anthony Batzler, Gregory D. Jenkins, Tracy L. Pietrzak, Erin E. Carlson, Matthew P. Goetz, Donald W. Northfelt, Edith A. Perez, Clark V. Williard, Daniel J. Schaid, Yusuke Nakamura, Richard M. Weinshilboum

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45 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)657-670
Number of pages14
JournalMolecular Endocrinology
Issue number4
Publication statusPublished - 01-04-2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology


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