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, butdepends onthe geneticbackground. The differencein incidenceof mammarytumors betweenBM-Blc-Trp53*'~ mice (susceptible) and C57BU6-Trp5y'~ mice (resistant) has allowed us to investigate genetic mechanisms that modify susceptibility to mammarytumors. We havedemonstrated that bothrecessive-acting anddominant-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 inmammarytumors andwas inherited as adominant trait. Therefore, BALB/c alleles appear to interferewith rates or fidelity of homology-directed repair of DMA double strand breaks. These observations provide a means to identify genes and pathwaysthat influence susceptibility to mammary tumors in mice.
SpecificAim 1 :Analysis of the effect of Dmbtlinsuppression of mammarytumors.
Aim1. 1: The effects ofDmbtl as a tumor suppressor gene will be examined. Expression constructs will be introduced into mammary epithelial cell lines andchanges intumor incidence will bemonitored.
Aim 1. 2: Expressionof DMBT1 protein innormal 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 ofthe 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 mammarytumors byaltering the rates or fidelity of DNArepair. Therefore, rates of DNA double strand break repair will be monitored using synthetic substrates. Identificationofgenes thatmodifysusceptibilitytomammarytumors willprovidemarkers for riskassessment andnovel targets for therapeutic intervention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CG (01))
Program Officer
Ogunbiyi, Peter
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Amherst
Veterinary Sciences
Schools of Earth Sciences/Natur
United States
Zip Code
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

Showing the most recent 10 out of 15 publications