My laboratory studies how genetic alteration of tumor suppressor gene pathways contribute to cancer initiation and progression. RB1, TP53, and PTEN are three of the most frequently altered tumor suppressor genes in aggressive human cancer, thus a well refined understanding of their function will facilitate development of novel approaches for cancer diagnosis and treatment. As an example, CDK4 inhibitors are now FDA approved for the treatment of breast cancer. The scientific foundation for this therapeutic approach is based, in part, on our discovery that the RB1 protein restricts cell cycle progression and our identification of CDK4 kinase as a key regulator of this activity. Thus, CDK4 inhibitors can be used to block cancer cell cycle progression for those tumors retaining an intact RB1 gene. More recently our lab has focused on identifying and dissecting additional molecular mechanisms utilized by these tumor suppressor genes to mediate their multi-faceted tumor suppressor activity. Emerging data from our lab and others indicate these tumor suppressor genes have non-canonical functions regulating cancer lineage plasticity and heterogeneity that make critical contributions to cancer progression and acquired therapeutic resistance. Our current interests are focused on elucidating the molecular basis of cancer lineage plasticity by manipulating these tumor suppressor genes in genetically engineered mouse models, patient derived organoids, and established cell lines. Leveraging this understanding, our goal is to develop therapeutic approaches to counter lineage plasticity to improve cancer patient outcomes.