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.
LaPlante CD, Bansal R, Dunphy KA, Jerry DJ, Vandenberg LN. J Endocr Soc. 2018 May 22;2(8):903-921. doi: 10.1210/js.2018-00024. eCollection 2018 Aug 1. Oxybenzone Alters Mammary Gland Morphology in Mice Exposed During Pregnancy and Lactation. PMID:30057971 Free PMC Article
Majewski AR, Chuong LM, Neill HM, Roberts AL, Jerry DJ, Dunphy KA. J Am Assoc Lab Anim Sci. 2018 Oct 12. doi: 10.30802/AALAS-JAALAS-18-000030. [Epub ahead of print] Sterilization of Silastic Capsules Containing 17β-Estradiol for Effective Hormone Delivery in Mus musculus. PMID:30314533
Jerry JD, Shull JD, Hadsell DL, Rijnkels M, Dunphy KA, Schneider SS, Vandenberg LN, Majhi PD, Byrne C, Trentham-Dietz A. 2018. Genetic variation in sensitivity to estrogens and breast cancer risk. Mammalian Genome. 29:24–37.
Majewski AR, Chuong LM, Neill HM, Roberts AL, Jerry JD, Dunphy KA. 2018. Sterilization of Silastic Capsules Containing 17β-Estradiol for Effective Hormone Delivery in Mus musculus. Journal of the American Association for Laboratory Animal Science.
LaPlante CD, Bansal R, Dunphy KA, Jerry JD, Vandenberg LN. 2018. Oxybenzone Alters Mammary Gland Morphology in Mice Exposed During Pregnancy and Lactation. Journal of the Endocrine Society. 2:903–921.
Schneider SS, Henchey EM, Sultana N, Morin SM, Jerry JD, Makari-Judson G, Crisi GM, Arenas RB, Johnson M, Mason HS et al.. 2017. Individual-specific variation in the respiratory activities of HMECs and their bioenergetic response to IGF1 and TNFa. Journal of Cellular Physiology. 232:2750–2765.
Le NDB, Tonga GY, Mout R, Kim S-T, Wille ME, Rana S, Dunphy KA, Jerry JD, Yazdani M, Ramanathan R et al.. 2017. Cancer Cell Discrimination Using Host–Guest “Doubled” Arrays. Journal of the American Chemical Society. 139:8008–8012.
Kundu N, Domingues CC, Chou C, Ahmadi N, Houston S, Jerry JD, Sen S. 2017. Use of p53-Silenced Endothelial Progenitor Cells to Treat Ischemia in Diabetic Peripheral Vascular Disease. Journal of the American Heart Association. 6:e005146.
Mak P, Li J, Samanta S, Chang C, Jerry JD, Davis RJ, Leav I, Mercurio AM. 2015. Prostate tumorigenesis induced by PTEN deletion involves estrogen receptor β repression.. Cell Rep. 10(12):1982-91.
Rotunno M, Sun X, Figueroa J, Sherman ME, Garcia-Closas M, Meltzer P, Williams T, Schneider SS, Jerry JD, Yang XR et al.. 2014. Parity-related molecular signatures and breast cancer subtypes by estrogen receptor status.. Breast Cancer Res. 16(4):R74.
Makari-Judson G, Braun B, Jerry JD, Mertens WC. 2014. Weight gain following breast cancer diagnosis: Implication and proposed mechanisms.. World J Clin Oncol. 5(3):272-82.
Sturgeon SR, Arcaro KF, Johnson MA, Balasubramanian R, Zorn M, Jerry JD, Schneider SS. 2014. DNA methylation in paired breast epithelial and white blood cells from women undergoing reduction mammoplasty.. Anticancer Res. 34(6):2985-90.
Dunphy KA, Seo J-H, Kim DJ, Roberts AL, Tao L, Direnzo J, Balboni AL, Crisi GM, Hagen MJ, Chandrasekaran T et al.. 2013. Oncogenic transformation of mammary epithelial cells by transforming growth factor beta independent of mammary stem cell regulation.. Cancer Cell Int. 13(1):74.
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. 4:e514.
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.
Yadava N, Schneider SS, Jerry JD, Kim C. 2013. Impaired mitochondrial metabolism and mammary carcinogenesis.. J Mammary Gland Biol Neoplasia. 18(1):75-87.
Jerry JD, Makari-Judson G, Crisi GM, Dunphy KA. 2013. Pregnancy offers new insights into mechanisms of breast cancer risk and resistance.. Breast Cancer Res. 15(5):312.
Petrocca F, Altschuler G, Tan SM, Mendillo ML, Yan H, Jerry JD, 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.