The Transforming Growth Factor Beta (TGF-ss) superfamily of growth factors regulates many cellular functions including cell growth, adhesion, migration, cell-fate determination and differentiation, and apoptosis. Ligands of the TGF-ss superfamily of growth factors comprises several TGF-ss isoforms, Activin isoforms, and Bone Morphogenetic Proteins, which are encoded by different genes but function through a similar receptor signaling system. The functionality of ligands, receptor proteins and SMAD intracellular messengers is critical for inhibitory signal transduction. There is, in this respect, growing evidence suggesting that common variants of the ligands, receptors and intracellular messengers of the TGF-ss superfamily may significantly modify breast cancer risk and outcome. We were the first to identify TGFBR1*6A, a common variant of the TGFBR1 gene. Our meta-analysis of fourteen case-control studies that included 6694 breast cancer cases and 8579 controls shows that TGFBR1*6A carriers have a significantly increased risk of breast cancer as compared with non- carriers. Overall, breast cancer risk is higher among TGFBR1*6A homozygotes (O.R. 1.40, 95% CI 1.04-1.88) than among TGFBR1*6A heterozygotes (O.R. 1.12, 95% CI 1.00-1.25) (Ptrend =8.41 x 10-4). A common variant of the TGFB1 gene has been associated with higher circulating levels of TGF-2 and increased TGF-ss secretion in vitro. A recent study conducted by the Breast Cancer Association Consortium (BCAC) has shown that breast cancer risk was increased among TGFB1 L10P heterozygotes (O.R. 1.07, 95% CI 1.02-1.13) and homozygotes (O.R. 1.16, 95% CI 1.08-1.25) (Ptrend = 2.8 x 10-5). Hence, naturally-occurring variants encoding for one ligand (TGFB1) and one receptor (TGFBR1) from the same signaling pathway are associated with breast cancer risk. These combined findings provide a strong rationale to comprehensively assess the TGF-2 signaling pathway in breast cancer. We propose to assess the association between haplotypes of the 65 genes of the TGF-2 superfamily and breast cancer risk using a family-based association study. Overall, we will perform a comprehensive genotypic analysis of the pathway in 5357 sister cases and sister controls from the NCI-sponsored Breast Cancer Family Registry. Genetic variants associated with breast cancer risk will be validated using the resources of BCAC. Validated SNPs will be further examined by the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. To search for the causal variant(s) we will 1) re-sequence the validated region(s) in 200 patients that carry the risk haplotypes, 2) perform dense SNP genotyping. Using RNA extracted from lymphoblastoid cell lines we will functionally characterize the putative functionally-relevant SNPs independently and jointly. In secondary analyses, we will evaluate whether the associations of the various haplotypes and functionally-relevant mutations with breast cancer risk differ according to tumor stage, ER/PR and ERBB2 status and menopausal status. We will also determine the association of the TGF-2 superfamily SNPs with breast cancer outcomes.

Public Health Relevance

There is growing evidence that subtle changes in genes of the TGF-2 pathway modify breast cancer risk. This project will study 65 genes of the TGF-2 pathway in 5357 women with breast cancer and their unaffected sisters and determine which genes are associated with breast cancer risk.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112520-10
Application #
8520198
Study Section
Special Emphasis Panel (ZRG1-PSE-G (02))
Program Officer
Seminara, Daniela
Project Start
2004-12-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$110,379
Indirect Cost
$28,866
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Pasche, Boris; Pennison, Michael J; Jimenez, Hugo et al. (2014) TGFBR1 and cancer susceptibility. Trans Am Clin Climatol Assoc 125:300-12
Principe, Daniel R; Doll, Jennifer A; Bauer, Jessica et al. (2014) TGF-?: duality of function between tumor prevention and carcinogenesis. J Natl Cancer Inst 106:djt369
Yi, Nengjun; Kaklamani, Virginia G; Pasche, Boris (2011) Bayesian analysis of genetic interactions in case-control studies, with application to adiponectin genes and colorectal cancer risk. Ann Hum Genet 75:90-104
Pasche, Boris; Absher, Devin (2011) Whole-genome sequencing: a step closer to personalized medicine. JAMA 305:1596-7
Kaklamani, Virginia; Yi, Nengjun; Sadim, Maureen et al. (2011) The role of the fat mass and obesity associated gene (FTO) in breast cancer risk. BMC Med Genet 12:52
Kaklamani, Virginia; Yi, Nengjun; Zhang, Kui et al. (2011) Polymorphisms of ADIPOQ and ADIPOR1 and prostate cancer risk. Metabolism 60:1234-43
Moore-Smith, Lakisha; Pasche, Boris (2011) TGFBR1 signaling and breast cancer. J Mammary Gland Biol Neoplasia 16:89-95
Bellam, Naresh; Pasche, Boris (2010) Tgf-beta signaling alterations and colon cancer. Cancer Treat Res 155:85-103
Pasche, Boris; Wisinski, Kari B; Sadim, Maureen et al. (2010) Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs. J Exp Clin Cancer Res 29:57
Pasche, Boris; Yi, Nengjun (2010) Candidate gene association studies: successes and failures. Curr Opin Genet Dev 20:257-61

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