Jill Bargonetti, PhD

To develop new ways to target triple-negative breast cancer, an aggressive form of breast cancer, and prevent its growth and metastasis.

Impact

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, a hallmark of aggressive cancers. 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.

Progress Thus Far

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. Using previously developed lab 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. In her most recent work, Dr. Bargonetti has been mapping how mtp53 collaborates with MDM2, MDM4, and PARP to suppress DNA repair, allowing cancer cells to survive and spread.

What’s next

Dr. Bargonetti and her team will continue to test how overexpression of MDM2 and MDMX influence DNA metabolism in breast cancer cells and thus sensitizes them to cell death by specific treatments. They will also determine how to target mutant p53 associated biomarkers, DNA changes that occur, and the tumor immune microenvironment signaling involved. In parallel, they will use their cell culture and breast cancer organoid models to test the combination of PARP pathway inhibition and radiation as a strategy to combat drug resistance and inhibit cancer cell survival and metastasis. Together, her research will improve our understanding of how this multi-protein network operates and uncover novel ways to exploit the mtp53-MDMX-MDM2 pathway, providing added therapeutic options for TNBC.