title: TGF-β signaling pathway and breast cancer susceptibility.
abstract: BACKGROUND
  TGF-β acts as a suppressor of primary tumor initiation but has been implicated as a promoter of the later malignant stages. Here associations with risk of invasive breast cancer are assessed for single-nucleotide polymorphisms (SNP) tagging 17 genes in the canonical TGF-β ALK5/SMADs 2&3 and ALK1/SMADs 1&5 signaling pathways: LTBP1, LTBP2, LTBP4, TGFB1, TGFB2, TGFB3, TGFBR1(ALK5), ALK1, TGFBR2, Endoglin, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6, and SMAD7 [Approved Human Gene Nomenclature Committee gene names: ACVRL1 (for ALK1) and ENG (for Endoglin)].
  
  
  METHODS
  Three-hundred-fifty-four tag SNPs (minor allele frequency > 0.05) were selected for genotyping in a staged study design using 6,703 cases and 6,840 controls from the Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) study. Significant associations were meta-analyzed with data from the NCI Polish Breast Cancer Study (PBCS; 1,966 cases and 2,347 controls) and published data from the Breast Cancer Association Consortium (BCAC).
  
  
  RESULTS
  Associations of three SNPs, tagging TGFB1 (rs1982073), TGFBR1 (rs10512263), and TGFBR2 (rs4522809), were detected in SEARCH; however, associations became weaker in meta-analyses including data from PBCS and BCAC. Tumor subtype analyses indicated that the TGFB1 rs1982073 association may be confined to increased risk of developing progesterone receptor negative (PR(-)) tumors [1.18 (95% CI: 1.09-1.28), 4.1 × 10(-5) (P value for heterogeneity of ORs by PR status = 2.3 × 10(-4))]. There was no evidence for breast cancer risk associations with SNPs in the endothelial-specific pathway utilizing ALK1/SMADs 1&5 that promotes angiogenesis.
  
  
  CONCLUSIONS
  Common variation in the TGF-β ALK5/SMADs 2&3 signaling pathway, which initiates signaling at the cell surface to inhibit cell proliferation, might be related to risk of specific tumor subtypes.
  
  
  CONCLUSIONS
  The subtype specific associations require very large studies to be confirmed.
authors.affiliation: Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, United Kingdom. serena.scollen@pfizer.com
authors.forename: Serena
authors.initials: S
authors.lastname: Scollen
authors.forename: Craig
authors.initials: C
authors.lastname: Luccarini
authors.forename: Caroline
authors.initials: C
authors.lastname: Baynes
authors.forename: Kristy
authors.initials: K
authors.lastname: Driver
authors.forename: Manjeet K
authors.initials: MK
authors.lastname: Humphreys
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.forename: Jonine
authors.initials: J
authors.lastname: Figueroa
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.forename: Paul D
authors.initials: PD
authors.lastname: Pharoah
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Robin
authors.initials: R
authors.lastname: Hesketh
authors.forename: James C
authors.initials: JC
authors.lastname: Metcalfe
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000209:etiology*; D016022:Case-Control Studies; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D016212:Transforming Growth Factor beta