TSPYL5 SNPs: association with plasma estradiol concentrations and aromatase expression

Mol Endocrinol. 2013 Apr;27(4):657-70. doi: 10.1210/me.2012-1397. Epub 2013 Mar 21.


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 ERα 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.

Trial registration: ClinicalTrials.gov NCT00283608.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aromatase / genetics*
  • Aromatase / metabolism
  • Base Sequence
  • Breast Neoplasms / blood
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Chromatin Immunoprecipitation
  • Chromosomes, Human, Pair 8 / genetics
  • Estradiol / blood*
  • Female
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic
  • Genetic Association Studies*
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • MCF-7 Cells
  • Molecular Sequence Data
  • Nuclear Proteins / genetics*
  • Nucleotide Motifs / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Promoter Regions, Genetic / genetics
  • Protein Binding / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • Nuclear Proteins
  • RNA, Messenger
  • TSPYL5 protein, human
  • Estradiol
  • Aromatase

Associated data

  • ClinicalTrials.gov/NCT00283608