Jill Bargonetti, PhD

2007-2008 BCRF Project:
Dr. Bargonetti and her colleagues have found that when estrogen receptor positive breast cancer cells have long-term exposure to estrogen, the p53 tumor suppressor pathway is compromised in part by the oncogenic protein Mdm2. Over the past year, with BCRF support, they provoked promising reactivation of some biochemical functions of p53 using the small molecule inhibitor of the p53-Mdm2 interaction, called Nutlin-3, in combination with the chemotherapeutic etoposide; activation of cancer cell death was not impressive. They achieved robust breast cancer cell killing with a stereo-chemically specific alkylating agent that is able to induce p53-independent and p53-dependent cell death, suggesting that protocols simultaneously activating p53-dependent and p53-independent cell death pathways are the most promising for killing breast cancer cells.

Dr. Bargonetti's goal for the coming year is to determine mechanisms for activating cell death in breast cancer cells with compromised p53 and to elucidate the mechanisms of inactivation of wild-type p53 in estrogen-influenced breast cancers. The need to identify drugs, and pathways, that induce cell death independently of p53 activity, or by the reactivation of compromised p53, deserves substantial attention. Despite the importance of p53-independent cell death and the potential for reactivation of p53 activity, little is known about the activation of such pathways.

Mid-Year Progress Report:
The mechanism by which estrogen promotes breast cancer is a serious concern and deserves substantial attention but the molecular mechanism of estrogen related tumor promotion has remained paradoxical. The Bargonetti group is resolving the paradox that estrogen can promote DNA damage but at the same time can promote increased cell survival. They found that when estrogen receptor positive breast cancer cells have long-term exposure to estrogen, the p53 tumor suppressor pathway is compromised in part by the oncogenic protein Mdm2. They see that estrogen acts as a tumor-promoting agent by promoting DNA damage and at the same time blocking the p53 pathway. While estrogen promotes DNA double strand breaks in estrogen receptor positive breast cancer cells it also provokes an increase in the oncogenic protein Mdm2 so that damage does not provoke cell death. This estrogen block to activation of the p53 pathway is against selective genes that are able to cause cell death and repair DNA.

The Bargonetti group has identified two key genes, puma and gadd45, that are selectively repressed as DNA damage inducible targets in the presence of estrogen. They also have achieved robust breast cancer cell killing with a stereo-chemically specific alkylating agent that can induce p53-independent cell death, in part by targeting (and depleting) the Chk1 kinase. This suggests that the down-regulation of Chk1 may be a promising target for killing breast cancer cells. The need to identify drugs, and pathways, that induce cell death independently of p53 activity, or by the reactivation of compromised p53, deserves substantial attention.

Bio:
Molecular biologist Jill Bargonett is a renowned cancer researcher, and innovator in the education of minorities in science. 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). Currently a Professor at Hunter College of the City University of New York, Professor Bargonetti has done extensive research on the p53 protein and the p53 gene, which assists in the suppression of tumor cells.

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 to determine if tumor promotion in humans results by inhibition of p53 production. They also examine if DNA damage caused by various chemotherapeutic drugs is able to bring about differential activation of p53 target genes as well as activate alternative cell death pathways that may facilitate killing cancer cells. 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 while it is associated with DNA in cancer cells.

Prior to arriving on the Hunter College campus in 1994, Bargonetti-Chavarria was a post-doctoral fellow at Columbia University (1990-1994). She was a visiting professor at Rockefeller University in 2002. Jill Bargonetti holds a M.S. and a Ph.D. in Molecular Biology, both from New York University (1987 and 1990 respectively) and a B.A. from SUNY Purchase. Awarded the prestigious Presidential Early Career Award for Scientists and Engineers by President Bill Clinton in 1997, Bargonetti has received numerous research grants from the National Science Foundation and the National Institutes of Health as well as grants from the American Cancer Society and the Department of Defense Breast Cancer Research program.

In 2001, she received a New York City Mayor's Award for Excellence in Science and Technology and an Outstanding Woman Scientist Award from the Association for Women in Science. She also received the 1998 New York Voice Award, given to those who have made a significant improvement to the quality of life in New York City, and the 1997 Kathy Keeton Mountain Top Award from the New York branch of the NAACP. In December 2004, Working Mother magazine profiled her as one of the nation's "Stellar Moms" and in May of 2005 both NYU and SUNY Purchase gave her distinguished Alumna awards.