Hunter College / City University of New York New York, New York
Hesselbach Professor Chair, Molecular, Cellular, and Development PhD Program Department of Biological Sciences Hunter College Belfer Research Building Graduate Center, City University of New York Adjunct Assistant Professor, Weill Cornell Medical College Department of Cell Biology
To develop new ways to target triple-negative breast cancer, an aggressive form of breast cancer, and prevent its growth and metastasis.
Triple-negative breast cancer (TNBC) is a group of diseases that are difficult to treat and have a high likelihood of spreading to other tissues, a process called metastasis. Part of the challenge is that TNBCs currently have few biomarkers that can be used to detect, diagnose, and manage it. TNBCs can evade DNA damaging agents such as PARP inhibitors by adapting their DNA damage repair system—this adaptation often results in genomic instability. Dr. Bargonetti is studying three critical biomarkers—mtp53, MDMX and MDM2—known to drive TNBC and other types of breast cancer to determine their role in this adaptation. Since these biomarkers correlate with increased sensitivity to PARP inhibitors, Dr. Bargonetti’s lab is focused on determining the molecular mechanisms involved in their interaction. These studies will potentially uncover novel ways to exploit the mtp53-MDMX-MDM2 axis and target the breast cancers that use it, providing druggable targets in a breast cancer subtype with limited therapeutic options.
Dr. Bargonetti has advanced the understanding of the role of mtp53, MDMX, and MDM2 in the spread of TNBC. Her work has shown that: 1) metastatic TNBCs that harbor a mutated p53 protein (mtp53) are sensitive to PARP inhibitors; 2) MDM2 and MDMX are often upregulated along with mtp53 in highly metastatic breast cancer; 3) upregulation of MDMX increases circulating tumor cells (CTCs) thereby facilitating TNBC metastasis; and 4) PARP inhibition promotes breast cancer cell death and correlates with a reduction in MDMX protein while MDM2 interacts with a critical DNA repair protein. The team has also developed laboratory models in which these proteins have been manipulated in order to further delve into how they influence PARP inhibitor sensitivity. Using these models, Dr. Bargonetti’s group showed that specific p53 mutations, or high expression of both mtp53 and PARP, are potential indicators of sensitivity to PARP inhibitor treatment.
Dr. Bargonetti and her team will continue to validate p53 gene mutations in breast cancers as potential biomarkers for sensitivity to PARP inhibitor-induced tumor cell death. The team is also testing how overexpression of MDM2 and MDMX influence DNA metabolism in breast cancer cells and thus sensitizes them to cell death by specific treatments. Dr. Bargonetti’s work suggests new potential breast cancer biomarkers for mtp53, overexpression of MDM2, and MDMX—this expands the biomarker list that can identify those cancers that will benefit from PARP inhibitor treatments and expands the spectrum of molecularly targetable breast cancer drivers.
The Breast Cancer Research Community has made a significant difference in my collaborations. The BCRF is by far the most exciting, collaborative, diverse, and knowledge generating international cancer research community. I am so fortunate to be a part of this amazing “brain trust” of wonderful people.
Jill Bargonetti, PhD has carried out extensive research on the wild-type p53 protein (which assists in the suppression of tumor cells) and oncogenic mutant p53 (which is a tumor promoter). She is also a leader in the field of MDM2 research, studying how MDM2 promotes breast cancer proliferation and the survival of circulating tumor cells. She received her B.A. from SUNY Purchase, her MS and PhD from New York University and her postgraduate training from Columbia University. In 1994, she joined the professoriate at The City University of New York (CUNY) at Hunter College and The Graduate Center in the PhD Programs of Biology and Biochemistry and currently holds the title of Full Professor at CUNY along with an adjunct professoriate appointment at the Weill Cornell Medical College in the Department of Cell Biology.
Dr. Bargonetti was awarded the prestigious Presidential Early Career Award for Scientists and Engineers by President Bill Clinton in 1997 and has received research grants from the American Cancer Society, The Department of Defense, The National Science Foundation (NSF), The National Institutes of Health (NIH), and the Breast Cancer Research Foundation (BCRF). 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) and served on the NIH Tumor Cell Biology study section from 2012-2018.
2005
The Estée Lauder Companies' Brands Award in Memory of Evelyn H. Lauder
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