title: TSPYL5 SNPs: association with plasma estradiol concentrations and aromatase expression.
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 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.
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Mohan
authors.initials: M
authors.lastname: Liu
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.forename: Aman U
authors.initials: AU
authors.lastname: Buzdar
authors.forename: Mark E
authors.initials: ME
authors.lastname: Robson
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.forename: Anthony
authors.initials: A
authors.lastname: Batzler
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Jenkins
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Pietrzak
authors.forename: Erin E
authors.initials: EE
authors.lastname: Carlson
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.forename: Donald W
authors.initials: DW
authors.lastname: Northfelt
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
authors.forename: Clark V
authors.initials: CV
authors.lastname: Williard
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Richard M
authors.initials: RM
authors.lastname: Weinshilboum
mesh_terms: D000368:Aged; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001943:Breast Neoplasms / Q000097:blood / Q000201:enzymology / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D004958:Estradiol / Q000097:blood*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D061986:MCF-7 Cells; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D059372:Nucleotide Motifs / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D012333:RNA, Messenger; C527859:TSPYL5 protein, human; D004958:Estradiol; D001141:Aromatase