Poster Presentation 29th Lorne Cancer Conference 2017

Targeting MDM4 to treat mutant p53 expressing Breast Cancer (#114)

Panimaya Jeffreena Miranda Alphonse Miranda 1 , Daniel Buckley 1 , Aart Jochemsen 2 , sue haupt 1 3 , ygal haupt 1 3 4 5
  1. Research Division, and Department of Pathology, Peter MacCallum Cancer Centre, parkville, melbourne, Victoria, Australia
  2. Department of Molecular Cell Biology, University Medical Centre, Leiden, The Netherlands
  3. Sir Peter MacCallum ,Department of Oncology, the University of Melbourne, Parkville, VIC, Australia
  4. Department of Pathology, the University of Melbourne, Parkville, VIC, Australia
  5. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia

Breast cancer (BrCa) is one of the most prevalent cancer types and second leading cause of cancer death among Australian women. The function or expression of the key p53 tumour suppressor protein is compromised frequently in cancers either by mutation or deregulation of its key negative regulators MDM2, an E3 ligase, or MDM4 a potent inhibitor of p53 activities. P53 mutation is associated with metastatic capacity and is most common in aggressive breast cancers with the worst prognosis. In our recent study we identified MDM4 as a potent negative regulator of wt p53 in breast cancer, and its depletion found to impede the growth of breast cancer cells, both in vivo and in vitro experimental models. Our screen of BrCa samples in a tissue microarray and cell lines using western blot has now shown elevated MDM4 expression in basal like and luminal BrCas that express mutant p53. This prompted us to test the contribution of MDM4 in oncogenesis breast cancers that express mutant p53. We have demonstrated that knock down (KD) of MDM4 in a range of breast cell lines (expressing mutant p53) across the subtypes impedes growth in culture. Studies are underway to identify the mechanism of growth inhibition stimulated by MDM4 depletions. The therapeutic potential of this approach was validated using a small molecule inhibitor of MDM4. Overall, our study demonstrates an essential role for MDM4 in the growth of breast cancer cells expressing mutant p53, and defines MDM4 as a potential novel therapeutic target in breast cancer.