A functional genetic variant in fragile-site gene FATS modulates the risk of breast cancer in triparous women

BMC Cancer

Research Article

Jun Zhang¹  Yawen Zhao²  Li Qiu²  Pan Xing²  Zheng Li²  Kexin Chen³  Fangfang Song³  Jiachun Lu⁴ 

[1] Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, P. R. China;Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, P. R. China;Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, P. R. China;Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, P. R. China;Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, P. R. China;Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, P. R. China;The Institute for Chemical Carcinogenesis, State Key Lab of Respiratory Disease, Guangzhou Medical University, 510182, Guangzhou, China;

关键词: Breast cancer;    FATS;    Single-nucleotide polymorphism;    p53;    Parity;   

DOI  :  10.1186/s12885-015-1570-9

 received in 2014-10-13, accepted in 2015-07-17,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundThe fragile-site associated tumor suppressor (FATS, formerly known as C10orf90), a regulator of p53-p21 pathway has been involved in the onset of breast cancer. Recent data support the idea that the crosstalk between FATS and p53 may be of physiological importance for reproduction during evolution. The aim of the current study was to test the hypothesis that FATS genetic polymorphism can influence the risk of breast cancer.MethodsWe conducted population-based studies in two independent cohorts comprising 1 532 cases and 1 573 controls in Tianjin of North China, and 804 cases and 835 controls in Guangzhou of South China, coupled with functional validation methods, to investigate the role of FATS genetic variant in breast cancer risk.ResultsWe identified a functional variant rs11245007 (905C > T, 262D/N) in fragile-site gene FATS that modulates p53 activation. FATS-262 N exhibited stronger E3 activity to polyubiquitinate p53 than did FATS-262D, leading to the stronger transcriptional activity of p53 and more pronounced stabilization of p53 protein and its activation in response to DNA damage. Case–control studies found that CT or TT genotype was significantly associated with a protective effect on breast cancer risk in women with parity ≥ 3, which was not affected by family history.ConclusionsOur findings suggest the role of FATS-p53 signaling cascade in suppressing pregnancy-related carcinogenesis and potential application of FATS genotyping in breast cancer prevention.

【 授权许可】

Unknown   
© Song et al. 2015. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.