Role of the Rb and p53 Tumor Suppressor Pathways in Mammary Tumorigenesis.

摘要

Understanding the genetic pathways that contribute to the development of specific breast cancer subtypes will lead to the discovery of more effective therapies. Two of the most common genetic alterations in human cancers involve inactivation of the Rb and p53 tumor suppressor pathways. To directly investigate the role of these pathways in breast cancer, we generated mice with conditional deletion of Rb and p53 in the mammary epithelium. Combined loss of Rb and p53 led to the development of tumors with features of epithelial-mesenchymaltransition (EMT) that are enriched for tumor-initiating activity. Microarray analysis revealed these tumors are similar to EMT-type tumors from other mouse mammary tumor models and the claudin-low subtype of human breast cancer. We have now begun using high-throughput chemical screens and and whole-genome lentiviral shRNA libraries to screen Rb/p53 deficient primary mouse mammary tumor cell lines for novel therapeutic targets.