TGF-β signaling pathway and breast cancer susceptibility

Serena Scollen, Craig Luccarini, Caroline Baynes, Kristy Driver, Manjeet K Humphreys, Montserrat Garcia-Closas, Jonine Figueroa, Jolanta Lissowska, Paul D Pharoah, Douglas F Easton, Robin Hesketh, James C Metcalfe, Alison M Dunning

Research output: Contribution to journalArticlepeer-review

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.

CONCLUSION: 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.

IMPACT: The subtype specific associations require very large studies to be confirmed.

Original languageEnglish
Pages (from-to)1112-9
Number of pages8
JournalCancer Epidemiology, Biomarkers and Prevention
Volume20
Issue number6
DOIs
Publication statusPublished - Jun 2011

Keywords

  • Aged
  • Breast Neoplasms
  • Case-Control Studies
  • Disease Susceptibility
  • Female
  • Humans
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Prospective Studies
  • Signal Transduction
  • Transforming Growth Factor beta

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