title: Functional variable number of tandem repeats variation in the promoter of proto-oncogene PTTG1IP is associated with risk of estrogen receptor-positive breast cancer.
abstract: Genetic polymorphisms in the signalling pathway of estrogen receptor (ER) could modify the risk of breast cancer. A variable number of tandem repeats (VNTR) polymorphism in the promoter of PTTG1IP, pituitary tumor transforming gene binding factor targeted by estrogen receptor α (ERα) in endocrine neoplasia, has been shown to be functional, but its relevance to cancer etiology was unknown. We investigated its association with breast cancer risk by genotyping in 658 patients and 866 controls and further analysed its differential interaction with ERα. We found nine types of alleles ranging from 2 to 9 and 11 repeats that form 29 distinct genotypes and 11 different biallelic repeat numbers. Subjects who carry the six-repeats allele (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.17-1.79), long alleles (≥6 repeats) (OR, 1.55; 95% CI, 1.17-2.05) or a high dose of biallelic repeats (OR, 1.38; 95% CI, 1.07-1.77) were at significantly increased risk of cancer. In stratification analysis, these associations consistently manifested in ER-positive breast cancer: in ER positive, PR-positive subtype, genotypes with the six-repeats allele (OR, 1.42; 95% CI, 1.06-1.90), long alleles (OR, 1.77; 95% CI, 1.17-2.67) or a high dose of biallelic repeats (OR, 1.67; 95% CI, 1.19-2.33) were associated with cancer risk; in ER positive, HER2-negative subtype, they were susceptible factors with the ORs being 1.46 (95% CI, 1.06-2.02), 2.06 (95% CI, 1.28-3.32) and 1.85 (95% CI, 1.26-2.71), respectively. Furthermore, functional analysis revealed that an increase in the number of tandem repeats enhances the binding affinity of ERα. The present study provides the first epidemiological evidence that functional regulatory variants of PTTG1IP were associated with the risk of ER-positive breast cancer, further supporting its relevance as one proto-oncogene in breast cancer.
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Chan
authors.initials: C
authors.lastname: Xiang
authors.forename: Haidong
authors.initials: H
authors.lastname: Gao
authors.forename: Lei
authors.initials: L
authors.lastname: Meng
authors.forename: Zhaoyu
authors.initials: Z
authors.lastname: Qin
authors.forename: Rong
authors.initials: R
authors.lastname: Ma
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Chengxue
authors.initials: C
authors.lastname: Dang
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Fuchu
authors.initials: F
authors.lastname: He
authors.forename: Haijian
authors.initials: H
authors.lastname: Wang
mesh_terms: D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D018598:Minisatellite Repeats; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D012307:Risk Factors; D020080:Tandem Repeat Sequences / Q000235:genetics
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047908:Intracellular Signaling Peptides and Proteins; C000715470:MAS1 protein, human; D008565:Membrane Proteins; C112633:PTTG1IP protein, human; D000090063:Proto-Oncogene Mas