Jill Bargonetti, PhD
Chair, Molecular, Cellular and Development PhD Subprogram in Biology
2012-2013 BCRF Project:
(made possible by generous support from The Estée Lauder Companies New York Area Employees in Memory of Evelyn H. Lauder)
CUNY Graduate Center
Professor, Department of Biological Sciences
New York, New York
Dr. Bargonetti's team is using genetically engineered tools to decrease the expression of three oncogenes (i.e. Mdm2, MdmX, and oncogenic mutant p53) because they hypothesize that these biomarkers are involved in the formation of different subtypes of breast cancer. The researchers discovered that reducing the amount of Mdm2 or mutant p53 protein in breast cancer cells reduces tumor growth and abnormal architecture in three-dimensional (3D) cell culture models. They identified that estrogen receptor positive (ER+) breast cancer cells possess an Mdm2-associated growth activation pathway that occurs in cells. Moreover, they uncovered that estrogen drives Mdm2-mediated breast cancer proliferation through a pathway previously unstudied in breast cancer.
In addition, Dr. Bargonetti and colleagues found that triple negative breast cancer cells with mutant p53 possess an oncogenic, gain-of-function, p53-DNA-protein interaction and increased cholesterol biosynthesis. In 2012-2013, they will also focus on triple negative breast cancers by discovering how mutant p53 drives changes in the breast cancer associated proteomes. The mutant p53 knockdown breast cancer cell lines this team developed are excellent tools for the discovery of new drug targets for triple negative breast cancers.
Mid-year Progress: During this grant period, Dr. Bargonetti's laboratory has made essential progress in two major areas of breast cancer research. The first is on the estrogen driven biomarker Mdm2. Dr. Bargonetti's team has found that Mdm2 promotes estrogen driven abnormal breast cancer architecture and may accomplish this by using the E2F pathway. This suggests that both Mdm2 and E2F may be good therapeutic targets to help induce cell death of estrogen fueled breast cancers. The second area of progress is on a biomarker for triple negative breast cancers, which is oncogenic mutant p53. The investigators have generated exciting preliminary data on signature proteins that are part of the triple negative oncogenic mutant p53 pathway and will further elucidate therapeutic targets to kill triple negative breast cancer effectively.
Molecular biologist Jill Bargonetti is a cancer researcher, and innovator in the education of minorities in science. Dr. Bargonetti began at Hunter College as an Assistant Professor in 1994 and is currently the Chair of the Molecular, Cellular and Development PhD Subprogram in Biology at the CUNY Graduate Center. Professor Bargonetti has done extensive research on the p53 protein and the p53 gene, which assists in the suppression of tumor cells. She was a member of the National Cancer Policy Board from 2002 until 2005 (a board of the Institution of Medicine and National Research Council of the National Academies).
As a post-doctoral research scientist at Columbia University she was a Damon Runyon Research Foundation grantee from 1991 until 1994 and contributed to a number of key discoveries in p53 biology. Working with Dr. Carol Prives she demonstrated that the mutant forms of p53 found in human cancers were incapable of binding to DNA while the wild-type version of the protein could bind site specifically to DNA (Bargonetti et al., Cell 1991). This result was one of the first indications that the wild-type protein did not promote tumorigenesis, but rather prevented it, i.e. the wild-protein acted as a tumor suppressor. They went on to be the first to show that wild-type p53 could activate transcription from an appropriate template in vitro but the tumor-derived mutant forms of p53 could not and that SV40 T antigen (the main transforming protein encoded by this virus) prevented transactivation by p53 (Farmer et al., Nature, 1992). She was first author on a publication that identified the DNA-binding domain of p53, this region was known to be the site of the vast majority of missense mutations in human cancers (Bargonetti et al., Genes Dev 1992). She was a co-author on the manuscript that showed p53 forms a tetramer (Friedman et al., PNAS, 1993) and used this observation to show that the missense mutant proteins acted in a dominant negative fashion by demonstrating that mixed protein tetramers could not bind DNA (Bargonetti et al., Genes Dev 1993). Her studies also provided an explanation for the physiological role of SV40 T antigen in tumorigenesis, by showing that it bound to p53 and prevented p53's binding to DNA (Bargonetti et al., Genes Dev 1992).
At Hunter's Center for the Study of Gene Structure and Function in the Department of Biological Sciences, she and her colleagues are currently working on defining effective ways to kill cancer cells that either have mutant p53 or dysfunctional p53 due to over-expression of the oncogenic protein Mdm2. These events happen in different sub-types of breast cancer as well as in other types of cancers. The work in her laboratory focuses on the molecular signal transduction pathways activated by various chemotherapeutic drugs to bring about differential activation of p53 target genes as well as to activate alternative p53-independent cell death pathways that facilitate killing resistant cancer cells. Presently this work is carried out using human cancer cell line models and with a C. elegans nematode model system. In addition, her research group investigates how an inherited single nucleotide polymorphism (SNP) in the mdm2 gene causes a predisposition to cancer by inactivating the p53 protein by increased production of an Mdm2 protein that remains associated with DNA in cancer cells. She has graduated ten PhD recipients who have worked on projects aimed at understanding mutant p53 gain-of-function activity, elucidating how p53 and Mdm2 function, as well as elucidating mechanisms to induce p53-independent cancer cell death. In addition numerous undergraduate students have worked with Dr. Bargonetti on research projects and she has trained many undergraduates on p53 biology in a combined laboratory and lecture required Biology major course in Molecular Genetics.