D. Joseph JerryAssociate Professor
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Research Interests
Tumor Suppressor Genes and the Cellular Basis for Susceptibility to Breast CancerReproductive factors and family history of breast cancer are the most important predictors of an individual’s risk of developing breast cancer. These observations emphasize the important contributions of both genetic background and hormonal exposures in determining the risk of breast cancer. Mutations in tumor suppressor genes (TP53, BRCA1, BRCA2) render the breast epithelium at increased risk of forming tumors. These genes have pivotal roles in sensing DNA damage and ensuring appropriate cellular responses. Hormones that stimulate proliferation and direct breast development have also been shown to increase risk of breast cancer. However, hormonal exposures accompanying a single full-term pregnancy diminishes lifetime risk of breast cancer by half. It is the goal of our laboratory to define the molecular pathways that mediate susceptibility and resistance to breast cancer and design targeted therapeutics to prevent breast cancer. Our laboratory has demonstrated an association between activity of the p53 tumor suppressor protein and incidence of mammary tumors. Expression and activity of p53 protein is responsive to hormonal stimuli and varies across different stages of mammary gland development. Therefore, a major focus of the laboratory is to discover the normal cellular mechanisms that regulate p53 expression and function and determine whether sustained elevation in p53 activity may prevent mammary tumors. Genetically engineered mice bearing targeted disruption of tumor suppressor genes and conditional overexpression of oncogenes are being used to identify factors that regulate p53 function. Genetic mapping strategies are also being used to identify low-penetrance modifiers of mammary tumor susceptibility that differ between strains of mice. Genes that regulate p53 function would provide novel targets for prevention and treatment of breast cancer. Through the use of contemporary techniques in molecular and cellular biology with animal models, we are defining the developmental biology of the breast epithelium itself, while providing both a genetic and cellular basis for susceptibility to breast cancer. |
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Selected PublicationsBecker, K.A., Lu, S.L., Dickinson, E.S., Dunphy, K.A., Mathews, L., Schneider, S.S. and Jerry, D.J. 2005. Estrogen and progesterone regulate radiation-induced p53 activity through TGF-? dependent pathways. Oncogene (Epub June 6, 2005) Minter L.M., Kuperwasser C.K., Dickinson E.S., and D.J. Jerry (2002) Cell-cycling status of mammary epithelial cells predicts p53 responsiveness to gamma-radiation. Development 129:2997-3008. Pub Med Abstract Jerry D.J., Minter L.M., Becker K.A., and A.C. Blackburn (2002)
Hormonal control of p53 and chemoprevention. Br. Cancer Res. 4:91-94.
PubMed
Abstract Kuperwasser C., Hurlbut G.D., Kittrell F.S., Medina D., Dickinson E.S., Naber S.P. and D.J. Jerry (2000) Development of spontaneous mammary tumors in BALB/c p53-heterozygous mice: A model for Li-Fraumeni syndrome. Am. J. Pathol. 157:2151-2159. PubMed Abstract Kuperwasser C., Pinkas J., Hurlbut G.D., Naber S.P., and D.J. Jerry (2000) Cytoplasmic sequestration and functional repression of p53 in mammary epithelium is reversed by hormonal treatment. Cancer Res. 60:2723-2729. PubMed Abstract Jerry D.J., Kittrell F.S., Kuperwasser C., Laucirica R., Dickinson E.S., Bonilla P.J., Butel J.S., and D. Medina (2000) A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development. Oncogene 19:1052-1058. PubMed Abstract Pinkas J., Butel J.S., Medina D. and D.J. Jerry (1999) Alternative splicing of the p53-binding domain in mdm2 during mammary tumorigenesis in the mouse. Int. J. Cancer 81:292-298. PubMed Abstract Jerry D.J., Kuperwasser C., Downing S., Pinkas J., He C., Dickinson E.S., Marconi S., and S.P. Naber (1998) Delayed involution of the mammary epithelium in BALB/c-p53null mice. Oncogene 17:2305-2312. PubMed Abstract Cibelli J.B., Stice S.L., Golueke P.J., Kane J.J., Jerry J., Blackwell C., Ponce de León F.A., and J.M. Robl (1998) Cloned transgenic calves produced from non-quiescent fetal fibroblasts. Science 280:1256-1258. PubMed Abstract
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The
mechanisms by which tumor suppressor genes regulate cancer susceptibility
are important to numerous cellular processes. These genes arbitrate
decisions of whether cells live or die in response to stress stimuli.
They also interact with basic cellular machinery that ensures integrity
of genomic DNA. These activities can be modulated to improve the efficiency
of genetic modification in somatic cells. These approaches together
with nuclear transplantation will make it possible to create genetically
engineered animals to produce biomedical compounds and cell-based therapeutics.
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