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Effect of functional variant rs11466313 on breast cancer susceptibility and TGFB1 promoter activity

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

This study aimed to investigate whether genetic polymorphisms in TGFB1 contribute to breast cancer (BC) susceptibility, and explore the mechanism of action.

Methods

A total of 7 tagging SNPs (tSNPs) were genotyped in 1161 BC cases and 1337 age-matched controls among Chinese Han population. Bioinformatics analysis was used to predict functional SNP closely linked to tSNPs. Luciferase gene reporter assay was performed to determine the effect of genetic variants on promoter activity. DNA pull-down assay and mass spectrometry were used to identify the differentially binding proteins to genetic variants.

Results

Genotyping analysis showed that rs1800469 (C>T) in the 5′ regulatory region of TGFB1 was associated with reduced BC risk. Bioinformatics analysis predicted that rs11466313 (-2389_-2391 Del/AGG) in the 5′ regulatory region of TGFB1, was closely linked to tSNP rs1800469 and could be functional. The genotyping of rs11466313 by PCR-SSCP showed that rs11466313 also conferred decreased BC risk. Luciferase assays demonstrated that rs11466313 minor allele reduced over ninefold of promoter activity compared with its major allele (p < 0.001). DNA pull-down assay and mass spectrometry revealed that rs11466313 minor allele lost the binding ability with FAM98B and HSP90B. Knocking down FAM98B but not HSP90B, the enhanced promoter activity driven by TGFB1 rs11466313 major allele was attenuated.

Conclusions

This study elucidates the impact of functional polymorphism rs11466313 in the regulatory region of TGFB1 on breast cancer susceptibility and gene expression, and could be helpful for future research to determine the value of this TGFB1 variant in the clinical setting.

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Funding

This study was funded by the National Natural Science Foundation of China (Nos. 81872382, 81672790 and 81621063).

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Authors and Affiliations

  1. Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Third Hospital, Peking University Health Science Center, Beijing, 100191, China

    Yan-Ting Zhou, Li-Yuan Zheng, Ya-Jun Wang, Li Yang, Ipsita Panda, Xin-Xia Tian & Wei-Gang Fang

  2. Breast Center, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142, China

    Yun-Tao Xie

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  1. Yan-Ting Zhou
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Correspondence to Xin-Xia Tian or Wei-Gang Fang.

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All procedures performed in studies involving human participants were approved by the Ethics Committee of Peking University Health Science Center and were in accordance with the 1964 Helsinki declaration.

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Informed consent was obtained from all individual participants included in the study. The Peking University IRB (reference No. IRB00001052-11029) approved this study.

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Zhou, YT., Zheng, LY., Wang, YJ. et al. Effect of functional variant rs11466313 on breast cancer susceptibility and TGFB1 promoter activity. Breast Cancer Res Treat 184, 237–248 (2020). https://doi.org/10.1007/s10549-020-05841-w

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