Breast cancer is a complex disease with both environmental and genetic factors contributing to an individual's risk of developing disease. Heritable mutations in TP53 have been associated with Li-Fraumeni syndrome in which breast cancer is the most common tumor. Mouse models of Li-Fraumeni syndrome also exhibit frequent mammary tumors, but depend on the genetic background. The difference in incidence of mammary tumors between BM-Blc-Trp53 +/- mice (susceptible) and C57BU6-Trp5y'~ mice (resistant) has allowed us to investigate genetic mechanisms that modify susceptibility to mammary tumors. We have demonstrated that both recessive-acting and dominant-acting susceptibility alleles contribute to mammary tumor susceptibility. A recessive-acting locus that acts as a suppressor of mammary tumors (SuprMaml) has been mapped to a 10 Mb region of mouse chromosome 7. In contrast, a recombination pathway mediated loss of heterozygosity at Trp53 in mammary tumors and was inherited as a dominant trait. Therefore, BALB/c alleles appear to interfere with rates or fidelity of homology-directed repair of DMA double strand breaks. These observations provide a means to identify genes and pathways that influence susceptibility to mammary tumors in mice.
Specific Aim 1 : Analysis of the effect of Dmbtl in suppression of mammary tumors.
Aim 1. 1: The effects of Dmbtl as a tumor suppressor gene will be examined. Expression constructs will be introduced into mammary epithelial cell lines and changes in tumor incidence will be monitored.
Aim 1. 2: Expression of DMBT1 protein in normal human breast tissues and tumors will be determined to assess the value of DMBT1 as a biomarker.
Specific Aim 2 : Genetic dissection of the effects of the SuprMaml locus on incidence of mammary tumors.
Aim 2. 1: The magnitude of the tumor suppressive effect of the SuprMaml locus on incidence of mammary tumors will be determined using in congenic mice.
Aim 2. 2: The interval will be subdivided in separate congenic mice to refine the location of the tumor suppressor activity.
Specific Aim 3 : Analysis of dominant-acting modifiers that alter rates of repair of DNA double strand breaks. Genetic background may influence susceptibility to mammary tumors by altering the rates or fidelity of DNA repair. Therefore, rates of DNA double strand break repair will be monitored using synthetic substrates. Identification of genes that modify susceptibility to mammary tumors will provide markers for risk assessment and novel targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA105452-01A1
Application #
6877239
Study Section
Special Emphasis Panel (ZRG1-CG (01))
Program Officer
Mietz, Judy
Project Start
2005-02-15
Project End
2010-01-31
Budget Start
2005-02-15
Budget End
2006-01-31
Support Year
1
Fiscal Year
2005
Total Cost
$309,026
Indirect Cost
Name
University of Massachusetts Amherst
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
Kundu, Nabanita; Domingues, Cleyton C; Chou, Cyril et al. (2017) Use of p53-Silenced Endothelial Progenitor Cells to Treat Ischemia in Diabetic Peripheral Vascular Disease. J Am Heart Assoc 6:
Böhringer, M; Obermeier, K; Griner, N et al. (2013) siRNA screening identifies differences in the Fanconi anemia pathway in BALB/c-Trp53+/- with susceptibility versus C57BL/6-Trp53+/- mice with resistance to mammary tumors. Oncogene 32:5458-70
Dunphy, Karen A; Schneyer, Alan L; Hagen, Mary J et al. (2011) The role of activin in mammary gland development and oncogenesis. J Mammary Gland Biol Neoplasia 16:117-26
Blackburn, Anneke C; Jerry, D Joseph (2011) Map making in the 21st century: charting breast cancer susceptibility pathways in rodent models. J Mammary Gland Biol Neoplasia 16:57-64
Compton, Shannon; Kim, Chul; Griner, Nicholas B et al. (2011) Mitochondrial dysfunction impairs tumor suppressor p53 expression/function. J Biol Chem 286:20297-312
Tao, Luwei; Roberts, Amy L; Dunphy, Karen A et al. (2011) Repression of mammary stem/progenitor cells by p53 is mediated by Notch and separable from apoptotic activity. Stem Cells 29:119-27
Jerry, D Joseph; Dunphy, Karen A; Hagen, Mary J (2010) Estrogens, regulation of p53 and breast cancer risk: a balancing act. Cell Mol Life Sci 67:1017-23
Yan, Haoheng; Blackburn, Anneke C; McLary, S Christine et al. (2010) Pathways contributing to development of spontaneous mammary tumors in BALB/c-Trp53+/- mice. Am J Pathol 176:1421-32
Bajaj, Avinash; Miranda, Oscar R; Phillips, Ronnie et al. (2010) Array-based sensing of normal, cancerous, and metastatic cells using conjugated fluorescent polymers. J Am Chem Soc 132:1018-22
Roy, Raghunath; Jerry, D Joseph; Thayumanavan, S (2009) Virus-inspired approach to nonviral gene delivery vehicles. Biomacromolecules 10:2189-93

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