Jill Bargonetti, PhD

2009-2010 BCRF Project:
(made possible by generous support from Estée Lauder)

Dr. Bargonetti's long-term goals are to determine mechanisms to activate cell death in breast cancer cells with compromised p53 and to elucidate the molecular mechanisms for inducing death in estrogen receptor positive versus triple-negative breast cancers using p53 status as a guide for entry points for treatment options.

She and her team will focus on the molecular targets blocking cell death using molecular predictive biomarkers for the determination of best practice personalized therapeutics of breast cancers. They will extend their studies which showed chemotherapeutics inducing p53-independent cell death killed estrogen receptor positive and negative cells, while viral delivery of stable expressing interfering RNAs got rid of p53, Mdm2 and MdmX and demonstrated the ability to make some estrogen receptor positive and triple-negative breast cancer cells sensitive to death stimuli.

Mid-Year Progress Report:
Dr. Bargonetti and colleagues have succeeded in generating, and characterizing, over 30 genetically engineered breast cancer cell lines for studying the mechanistic participation of oncogenes, Mdm2, MdmX and gain of function mutant-p53, in breast cancer cell proliferation. These genetically engineered cell lines are marked by expression of a green fluorescent protein. The researchers examined estrogen receptor positive (ER+) breast cells with a predictive marker in the mdm2 gene and triple negative breast cells with predictive mutations in the p53 gene. The inducible knockdown of oncogenes Mdm2 or mutant-p53 in the breast cancer sub-types has enabled them to determine critical pathways in the progression towards oncogenesis.

Their studies show that silencing the oncogenes Mdm2 and mutant-p53 in breast cancer results in cellular changes that associate with reduced oncogenic capacity. In addition pre-clinical tests with 8-amino-adenosine suggest they have identified a nucleoside analogue that can kill aggressive, oncogenic mutant p53 containing, triple negative breast cancer cells. They predict that the inducible knockdown cell lines they have generated will become valuable tools for the breast cancer research community and that increasing the current breast cancer biomarkers to include Mdm2 and mutant-p53 will aid "personalized" treatments for breast cancers.

Bio:
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 a tenured Professor at the City University of New York with appointments at Hunter College in the Department of Biological Sciences and at The Graduate Center in the Departments of Biology and Biochemistry. 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 nine Ph.D. 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.