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BCRF Grantee Since

2005

Donor Recognition

The Estée Lauder Companies Brands Award in Memory of Evelyn H. Lauder

Area(s) of Focus

Jill Bargonetti, PhD

Chair, Molecular, Cellular and Development PhD Subprogram in Biology
CUNY Graduate Center
Professor, Department of Biological Sciences
Hunter College
New York, New York

Current Research

Dr. Bargonetti’s team is determining the protein targets required for estrogen driven MDM2 associated phenotypes in estrogen receptor-positive (ER+) breast cancers and the protein targets required for mutant p53 driven phenotypes in triple negative breast cancers (TNBCs). They have established a collaboration with the proteomics group at Memorial Sloan-Kettering Cancer Center to determine the breast cancer proteomic targets of MDM2 and oncogenic mutant p53. For these studies, Dr. Bargonetti plans to use her genetically engineered breast cancer cell lines that allow her team to selectively remove these cancer associated biomarkers so that they can directly determine the associated MDM2 and mutant p53 pathways. This collaboration enabled Dr. Bargonetti to be the first to confirm the previously identified cholesterol biosynthesis pathway as a proteomic target of mutant p53 and to discover over 60 new and previously unidentified protein targets regulated in the cytoplasm. One of the newly identified mutant p53 targets detected was PARP. This is particularly exciting because PARP is a biomarker currently being examined as a pharmacogenomic therapeutic. Using the same methods as they have successfully used for identifying the novel protein targets of mutant p53, Dr. Bargonetti and her team will identify the novel breast cancer protein targets of MDM2. She uncovered a previously unidentified estrogen-driven breast cancer pathway that utilizes increased MDM2 protein to drive abnormal mammary architecture and looks forward to finding the novel protein targets responsible for tumorigenesis.

Mid-Year Summary

Dr. Bargonetti’s laboratory is determining the protein targets required for estrogen driven MDM2 associated oncogenic traits in ER+ breast cancers and the protein targets required for mutant p53 driven metastasis of triple negative breast cancers (TNBCs). Breast cancer cells grown in a 3D matrigel system recapitulate metastatic characteristics. The researchers found that these metastatic traits were reverted by depleting either mutant p53 in triple negative breast cancers or MDM2 in estrogen driven subtypes. Using a proteomics approach they identified that one of the potential protein drivers of metastasis signaled to by mutant p53 is an adhesion protein called Paxillin. They are currently validating Paxillin as a mutant p53 target and examining this adhesion driven pathway as a target for reverting abnormal mammary architecture and inhibiting certain types of metastatic breast cancer.

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 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.