TGF-β signaling pathway and breast cancer susceptibility.

نویسندگان

  • 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
چکیده

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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Effects of fibromodulin protein expression on NFkB and TGFβ signaling pathways in liver cancer cells

Introduction: The incidence rate of liver cancer is continuously increasing. Currently, gene therapy is applied to improve various medical issues such as cancer treatment approaches. Correspondingly, fibromodulin involves in many biological and physiological processes through interaction with growth factors and signaling pathway receptors. The aim of this study was to investigate the effects of...

متن کامل

Directed Blocking of TGF-β Receptor I Binding Site Using Tailored Peptide Segments to Inhibit its Signaling Pathway

Background: TGF-β isoforms play crucial roles in diverse cellular processes. Therefore, targeting and inhibiting TGF-β signaling pathway provides a potential therapeutic opportunity. TGF-β isoforms bind and bring the receptors (TβRII and TβRI) together to form a signaling complex in an ordered manner. Objectives: Herein, an antagonistic variant of TGF-β (AnTβ)...

متن کامل

TGF-β1 enhanced myocardial differentiation through inhibition of the Wnt/β-catenin pathway with rat BMSCs

Objective(s): To investigate and test the hypotheses that TGF-β1 enhanced myocardial differentiation through Wnt/β-catenin pathway with rat bone marrow mesenchymal stem cells (BMSCs).Materials and Methods: Lentiviral vectors carrying the TGF-β1 gene were transduced into rat BMSCs firstly. Then several kinds of experimental methods were u...

متن کامل

LAT-derived microRNAs in HSV-1 target SMAD3 and SMAD4 in TGF-β/Smad signaling pathway

Background: During its latent infection, HSV-1 produces only a miRNA precursor called LAT, which encodes six distinct miRNAs. Recent studies have suggested that some of these miRNAs could target cellular mRNAs. One of the key cell signaling pathways that can be affected by HSV-1 is the TGF-β/Smad pathway. Herein, we investigated the potential role of the LAT as well as three LAT-derived miRNAs ...

متن کامل

TGF‐β transactivates EGFR and facilitates breast cancer migration and invasion through canonical Smad3 and ERK/Sp1 signaling pathways

Transforming growth factor-beta (TGF-β) functions as a potent proliferation inhibitor and apoptosis inducer in the early stages of breast cancer, yet promotes cancer aggressiveness in the advanced stages. The dual effect of TGF-β on cancer development is known as TGF-β paradox, and the remarkable functional conversion of TGF-β is a pivotal and controversial phenomenon that has been widely inves...

متن کامل

Pathway analyses identify TGFBR2 as potential breast cancer susceptibility gene: results from a consortium study among Asians.

BACKGROUND The TGF-β signaling pathway plays a significant role in the carcinogenic process of breast cancer. METHODS We systematically evaluated associations of common variants in TGF-β signaling pathway genes with breast cancer risk using a multistage, case-control study among Asian women. RESULTS In the first stage, 341 single-nucleotide polymorphisms with minor allele frequencies ≥ 0.05...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

دوره 20 6  شماره 

صفحات  -

تاریخ انتشار 2011