The p27Kipl Tumor Suppressor and Multi-Step Tumorigenesis

The cell cycle inhibitor p27kip1 has been implicated in a wide array of human cancers, including breast cancer. The overall goal of this research is to understand the role of p27kip1 as a tumor suppressor by studying the interaction of p27 with other genes, particularly p130, a member of the Retinoblastoma protein family, in multi-step cancer. We have used insertional mutagenesis in p27-null mice to create a model of p27- associated lymphomas and have identified myc genes and several candidate loci as p27- collaborating gene activations. We have also bred p27/p130 double null mice to study the interaction of these two genes in tumor suppression. We have also developed an experimental strategy to study the role of p27-loss in mammary carcinogenesis in mice. Finally we have analyzed pl3O expression more than 100 primary human breast cancers. Understanding these genetic pathways may lead to mechanistic insights into the tumor suppressor function of p27kip 1, as well as new therapeutic approaches to p27kip- associated cancers.