• Open Access

Functional variable number of tandem repeats variation in the promoter of proto-oncogene PTTG1IP is associated with risk of estrogen receptor-positive breast cancer

Authors

  • Chan Xiang,

    1. State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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    • These authors contributed equally to this work.
  • Haidong Gao,

    1. Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China
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    • These authors contributed equally to this work.
  • Lei Meng,

    1. Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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    • These authors contributed equally to this work.
  • Zhaoyu Qin,

    1. State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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  • Rong Ma,

    1. Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China
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  • Yang Liu,

    1. State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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  • Yan Jiang,

    1. State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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  • Chengxue Dang,

    1. Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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  • Li Jin,

    1. State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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  • Fuchu He,

    Corresponding author
    1. State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China
    • State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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  • Haijian Wang

    Corresponding author
    • State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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To whom correspondence should be addressed. E-mail: haijianwang@fudan.edu.cn; hefc@nic.bmi.ac.cn

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. (Cancer Sci 2012; 103: 1121–1128)

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