D. Joseph Jerry, Ph.D.

Regulation of the p53 Tumor Suppressor Gene and Susceptibility to Breast Cancer.

Reproductive factors and family history of breast cancer are among the most consistent 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. 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.

The p53 tumor suppressor protein is a major focus of the laboratory because its pivotal role in cancer. In addition to its role in genome surveillance, we found that loss of p53 allows expansion of the mammary stem cell population and this can be reversed by inhibition of Notch. Surprisingly, the fundamental actions of p53 on genome surveillance are enhanced by hormonal stimuli during pregnancy and contribute to the reduction in mammary tumors afforded by a full-term pregnancy. Administration of exogenous estrogen was sufficient to mimic the effect of pregnancy. Although estrogen stimulates proliferation, it also potentiates the p53-mediated apoptosis. These duplicitous actions of estrogens appear to be regulated through distinct estrogen receptors. Therefore, selective activation of the genome surveillance actions can be harnessed for the prevention of breast cancer and adjuvant therapies for those tumors with functional p53.

The frequent mutation of p53 in breast cancer reflects its critical role. However, in mice bearing mutations in p53, the incidence of mammary tumors differs dramatically among strains. Naturally-occurring variants in homology-directed DNA repair have revealed a profound role for this pathway in determining risk of mammary tumors. We are also determining gene expression profiles premalignant breast lesions. These studies provide the basis for diagnostic tests defining which patients are at high risk and should consider treatments while also providing insights into the molecular basis for premalignancy in the human breast.

 

Research Affiliations:

Rays of Hope Center for Breast Cancer Research

Institute for Applied Life Sciences 

Breast Cancer & Environment Research Program (BCERP) 

Selected Papers:

Mak, P., Li, J., Samanta, S., Chang, C., Jerry, D.J., Davis, R.J., Leav, I., and Mercurio, A.M. 2015. Prostate Tumorigenesis Induced by PTEN Deletion Involves Estrogen Receptor β Repression. Cell Reports PMID: 25818291; PMCID: PMC4382442.

Rotunno, M., Sun, X., Figueroa, J., Sherman, M.E., Montserrat, G.-C., Meltzer, P., Williams, T., Schneider, S.S., Jerry, D.J., Yang, X.R., Troester, M. 2014. Parity-related molecular signatures and breast cancer subtypes by estrogen receptor status. Breast Cancer Res. 8;16(4):R74. PMID: 25005139.

Makari-Judson G, Braun B, Jerry DJ, Mertens WC. 2014. Weight gain following breast cancer diagnosis: Implication and proposed mechanisms. World J Clin Oncol. 5(3):272-82. doi: 10.5306/wjco.v5.i3.272. PMID: 25114844.

Sturgeon SR, Arcaro KF, Johnson MA, Balasubramanian R, Zorn M, Jerry DJ, Schneider SS. 2014. DNA methylation in paired breast epithelial and white blood cells from women undergoing reduction mammoplasty. Anticancer Res. 34(6):2985-90.; PMID: 24922663.

Jerry, DJ, Makari-Judson, G, Crisi, GM, and Dunphy, KA. 2013. Pregnancy offers new insights into mechanisms of breast cancer risk and resistance. Br. Cancer Res. PMID: 24060354; PMCID: PMC3979118.

Petrocca F, Altschuler G, Tan SM, Mendillo ML, Yan H, Jerry DJ, Kung AL, Hide W, Ince TA, Lieberman J. 2013. A genome-wide siRNA screen identifies proteasome addiction as a vulnerability of basal-like triple-negative breast cancer cells. Cancer Cell 24(2):182-96. doi: 10.1016/j.ccr.2013.07.008. PMID: 23948298.

Dunphy, K.A., Seo, J.-H., Kim, D.J., Roberts, A.L., Tao, L., DiRenzo, J., Balboni, A.L., Crisi, G.M., Hagen, M.J., Chandrasekaran, T., Gauger, K.J., Schneider, S.S. and Jerry, D.J. 2013. Oncogenic transformation of mammary epithelial cells by Transforming Growth Factor beta independent of mammary stem cell regulation. Cancer Cell Int. Cancer Cell Int. 2013 Jul 25;13(1):74. PMID: 23883065; PMCID: PMC3733955.

Decastro AJ, Dunphy KA, Hutchinson J, Balboni AL, Cherukuri P, Jerry DJ, Direnzo J. 2013. MiR203 mediates subversion of stem cell properties during mammary epithelial differentiation via repression of ΔNP63α and promotes mesenchymal-to-epithelial transition. Cell Death Dis. 28;4:e514. PMID: 23449450; PMCID: PMC3734833.

Böhringer M, Obermeier K, Griner N, Waldraff D, Dickinson E, Eirich K, Schindler D, Hagen M, **Jerry DJ, **Wiesmüller L. 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(48):5458-70.; PMID: 23435420; PMCID: PMC3898496 (**Co-corresponding authors).

Pirone, J.R., D’Arcy,M., Stewart, D.A., Hines, W.C., Johnson, M.A., Gould, M.N., Yaswen, P., Jerry, D.J., Schneider, S.S., Troester, M.A. 2012. Age-associated gene expression in normal breast tissue mirrors qualitative age-at-incidence patterns for breast cancer. Cancer Epidemiol. Biomarkers Prev. 21(10):1735-44. PMID: 22859400; PMCID: PMC3684707.

Sun X, Casbas-Hernandez P, Bigelow C, Makowski L, Jerry DJ, Smith Schneider S, Troester MA. 2012. Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression.  Breast Cancer Res Treat. 131(3):1003-12. PMID: 22002519; PMCID: PMC3640411.

Compton, S., Kim, C., Griner, N.B., Porluri, P., Scheffler, I.E., Sen, S., Jerry, D.J., Schneider, S., and Yadava, N. 2011. Mitochondrial dysfunction impairs tumor suppressor p53 expression/function. J. Biol. Chem. 286(23):20297-312. PMID: 21502317  PMCID: PMC3121470.

Nguyen, D.H., Oketch-Rabah, H.A., Illa-Bochaca, I., Geyer, F.C., Reis-Filho, J.S., Mao, J.-H., Ravani, S.A., Zavadil, J., Borowsky, A.D., Jerry, D.J., Dunphy, K.A., Seo, J.H., Haslam, S., Medina, D., and Barcellos-Hoff, M.H. 2011. Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease breast cancer latency and affect tumor type. Cancer Cell 19(5):640-51. PMID: 21575864 PMCID: PMC3110779.

Tao, L., Roberts, A.L., Dunphy, K.A., Bigelow, C., Yan, H., and Jerry, D.J. 2011. Repression of mammary stem/progenitor cells by p53 is mediated by notch and separable from apoptotic activity. Stem Cells 29(1):119-27. PMID: 21280161; PMCID: PMC3404152.

Dunphy, K.A., Tao, L., and Jerry, D.J. 2010. Mammary epithelial transplant procedure. J. Vis. Exp. 10;(40). doi: 10.3791/1849. PMID: 20548284; PMCID: PMC3153903.

Bajaj, A., Miranda, O.R., Phillips, R., Kim, I.-B., Jerry, D.J., Bunz, U.H., and Rotello, V.M. 2010. Array-based sensing of normal, cancerous and metastatic cells using conjugated fluorescent polymers. J. Am. Chem. Soc. 132(3):1018-22.PMID: 20039629, PMCID: PMC2810251.

Yan, H., Blackburn, A.C., McLary, S.C., Tao, L., Roberts, A.L., Xavier, E.A., Dickinson, E.S., Seo, J.H., Arenas, R.B., Otis, C.N., Cao, Q.J., Lawlor, R.G., Osborne, B.A., Kittrell, F.S., Medina, D. and Jerry, D.J. 2010. Pathways contributing to development of spontaneous mammary tumors in BALB/c-Trp53+/- mice. Am. J. Pathol. 176(3):1421-32. PMID: 20110418; PMCID: PMC2832161.

Jerry, D.J., Dunphy, K.A., and Hagen, M.J. 2010. Estrogens, regulation of p53 and breast cancer risk: A balancing act.  Cell Mol Life Sci. (Invited for “Visions and Reflections” section) 67(7):1017-23.PMID: 20238478.

Troester, M.A. Lee, M.H., Carter, M., Fan, C., Cown, D.W., Perez, E.R., Pirone, J.R., Perou, C.M., Jerry, D.J., Schneider, S.S.. 2009. Activation of Host Wound Responses in Breast Cancer Microenvironment. Clin. Cancer Res.15(22):7020-7028. PMID: 19887484, PMCID: PMC2783932.

Bajaj, A., Miranda, O.R., Kim, I.B., Philips, R.L., Jerry, D.J., Bunz, U., Rotello, V.M. 2009. Detection and differentiation of normal, cancerous, and metastatic cells using nanoparticle-polymer sensor arrays. Proc. Natl. Acad. Sci. USA 106(27):10912-6. PMID: 19549846, PMCID: PMC2708737.

Lu, S., Becker, K.A., Hagen, M.J., Yan, H., Roberts, A.L., Mathews, L.A., Schneider, S.S., Siegelmann, H.T., MacBeth, K.J., Tirrell, S.M., Blanchard, J.L. and Jerry, D.J. 2008. Transcriptional responses to estrogen and progesterone in mammary gland identify networks regulating p53 activity. Endocrinology. 149(10):4809-20. PMID: 18556351, PMCID: PMC2582927.

Dunphy, K.A., Blackburn, A.C., Yan, H., O’Connell, L.R., and Jerry, D.J. 2008. Estrogen and Progesterone Induce Persistent Increases in p53-Dependent Apoptosis and Suppress Mammary Tumors in BALB/c-Trp53+/- Mice. Br. Cancer Res. 10(3):R43. PMID: 18471300, PMCID: PMC2481490.

Samanta, B., Yan, H., Fischer, N.O., Shi, J., Jerry, D.J., Rotello, V.M. 2008. Protein-passivated Fe3O4 Nanoparticles: Low Toxicity and Rapid Heating for Thermal Therapy. J. Materials Chem. 18(11):1204-1208. PMID: 19122852, PMC2593465.

Blackburn, A.C., Hill, L.Z., Roberts, A.L., Wang, J., Aud, D., Jung, J., Nikolcheva, T., Allard, J., Peltz, G. Otis, C.N., Cao, Q. J., Ricketts, R.S., Naber, S.P., Mollenhauer, J., Poustka, A., Malamud, D., and Jerry, D.J. 2007. Genetic mapping in mice identifies DMBT1 as a candidate modifier of mammary tumors and breast cancer risk. Am. J. Pathol. 170(6):2030-41. PMID: 17525270, PMC1899446.

Becker, K.A., Lu, S., 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-β dependent pathways. Oncogene 24(42):6345-6353. PMID: 15940247.

Blackburn, A.C., McLary, S.C., Naeem, R., Luszcz, J., Stockton, D.W., Donehower, L.A., Mohammed, M., Mailhes, J.B., Soferr, T., Naber, S.P., Otis, C.N., and Jerry, D.J. 2004. Loss of heterozygosity occurs via mitotic recombination in Trp53+/- mice and associates with mammary tumor susceptibility of the BALB/c strain. Cancer Res. 64(15):5140-5147.  PMID: 15289317.

Blackburn, A.C., Brown, J.S., Naber, S.P., Otis, C.N., Wood, J.T., and Jerry, D.J. 2003. BALB/c alleles for Prkdc and Cdkn2a interact to modify tumor susceptibility in Trp53+/- mice. Cancer Res. 63(10):2364-2368. PMID: 12750252.

Jerry, D.J., Kittrell, F.S., Kuperwasser, C., Laucirica, R., Dickinson,E.S., Bonilla, P.J., Butel, J.S., and Medina, D. 2000. A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development. Oncogene 19(8):1052-1058. PMID: 10713689.

Kuperwasser, C. Hurlbut, G.D., Kittrell, F.S., Dickinson, E.S., Laucirica, R., Medina, D., Naber, S.P. and Jerry, D.J.  2000.  Development of spontaneous mammary tumors in BALB/c p53-heterozygous mice: A model for Li-Fraumeni syndrome.  Am. J. Pathol.  157(6):2151-2159. PMID: 11106587; PMCID: PMC1885755.

Jerry, D.J., Kuperwasser, C., Downing, S.R., Pinkas, J., He, C., Dickinson, E., Marconi, S., and Naber, S.P. 1998. Delayed involution of the mammary epithelium in BALB/c-p53null mice.  Oncogene 17(18):2305-2312. PMID: 9811461.