title: A functional genetic variant in fragile-site gene FATS modulates the risk of breast cancer in triparous women.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Our findings suggest the role of FATS-p53 signaling cascade in suppressing pregnancy-related carcinogenesis and potential application of FATS genotyping in breast cancer prevention.
authors.affiliation: Department of Epidemiology and Biostatistics, , Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China. double1980@163.com.|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, Tianjin, 300060, P. R. China. double1980@163.com.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China. doctorjunzhang@163.com.|Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China. doctorjunzhang@163.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China. nangongningchen@163.com.|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, Tianjin, 300060, P. R. China. nangongningchen@163.com.
authors.forename: Li
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China. yawenzhao1989@163.com.|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, Tianjin, 300060, P. R. China. yawenzhao1989@163.com.
authors.forename: Yawen
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China. xingpan1314@126.com.|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, Tianjin, 300060, P. R. China. xingpan1314@126.com.
authors.forename: Pan
authors.initials: P
authors.lastname: Xing
authors.affiliation: The Institute for Chemical Carcinogenesis, State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, 510182, China. jcLu@gzhmc.edu.cn.
authors.forename: Jiachun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Epidemiology and Biostatistics, , Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China. chenkexin@tjmuch.com.|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, Tianjin, 300060, P. R. China. chenkexin@tjmuch.com.
authors.forename: Kexin
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China. zhengli@tijmu.edu.cn.|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, Tianjin, 300060, P. R. China. zhengli@tijmu.edu.cn.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
mesh_terms: D044466:Asian People / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002681:China; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D061986:MCF-7 Cells; D010298:Parity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C556020:C10orf90 protein, human; D003598:Cytoskeletal Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53