We were the first to identify TGFBR1*6A, a common variant of the TGFBR1 gene (which encodes the type I TGF-beta receptor). We have shown that TGFBR1*6A transmits TGF-beta growth inhibitory signals significantly less effectively than does TGFBR1. In a meta-analysis of the three case-control studies published on TGFBR1*6A and breast cancer that include 555 cases and 1033 controls, 21.1% of cases and 13.6% of controls were TGFBR1*6A carriers and TGFBR1*6A was significantly associated with breast cancer (OR 1.48, CI 1.11-1.96). A common variant within the human TGF-beta1 (TGFB1) gene itself is represented by the substitution of Leucine to Proline (T-C) at the 10th amino acid position (T29C). The T-> C substitution results in higher extracellular TGFB1 secretion and higher circulating levels of TGFB1 have been observed in humans who carry the C allele. Investigation of this polymorphism with regard to breast cancer risk has yielded conflicting results. We propose to assess the individual and combined association between these two well-characterized and functionally relevant TGF-beta signaling pathway variants and breast cancer risk using a family-based association study comparing genotypes in 1844 women with breast cancer to those of their 2547 unaffected sisters. We have the following Specific Aims: 1) To assess the association between carrier status of the TGFBR1*6A allele and breast cancer risk. Hypothesis: carrier status of this allele is associated with increased risk of breast cancer. 2) To assess the association between the other functionally relevant variant of the TGF-beta signaling pathway, TGFB1 T29C and breast cancer risk. Hypothesis: carrier status of the T allele is associated with increased risk of breast cancer. 3) To assess the combined effects of TGFBR1 and TGFB1 variants that affect TGF-beta signaling on breast cancer risk. Hypothesis: Individuals with the lowest predicted levels of TGF-beta signaling, i.e. carriers of both the TGFB1 *T allele and the TGFBR1 *6A allele have a increased risk of breast cancer compared to individuals with the lowest predicted levels of TGF-beta signaling, i.e. homozygotes for both the TGFB1*C allele and the TGFBR1*9A allele.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112520-04
Application #
7465351
Study Section
Special Emphasis Panel (ZRG1-HOP-N (02))
Program Officer
Seminara, Daniela
Project Start
2005-09-07
Project End
2008-10-31
Budget Start
2008-07-01
Budget End
2008-10-31
Support Year
4
Fiscal Year
2008
Total Cost
$145,780
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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