Breast Cancer, Tumor Suppressors and Targeted Therapy
Our group employs molecular biology and mouse genetics to decipher mechanisms of cancer, in particular breast cancer, and identify dependencies that can be exploited for therapy. A major focus is the tumor suppressors RB1, PTEN and TP53. In breast cancer, one highly aggressive subtype, called triple negative breast cancer, is driven by mutation/loss of TP53 together with RB1 or PTEN. Our lab has generated mouse models in which p53/Rb or p53/Pten are deleted specifically in the mammary epithelium, and identified unique vulnerabilities of these tumors, as well as human breast cancer lines with mutations in these tumor suppressors. We are using transposon-mediated mutagenesis to identify oncogenic networks that cooperate with Rb and p53 to induce metastatic disease, and induce resistance to therapy. We are also studying the role of Rb is reprogramming cellular metabolism both in breast cancer and Medulloblastoma.
Another highly aggressive breast cancer subtype is driven by over-expression/ amplification of the receptor tyrosine kinase HER2/ERBB2/NEU. Using a mouse model for this disease, MMTV-Her2/Neu (Bill Muller), we developed a prognostic signature that can predict clinical outcome for HER2+:ERa- breast cancer patients. Through kinome shRNA library screens, we have also identified targets that are preferentially required for HER2+ breast cancer stem cells. Our goal over the next few years is to move these basic findings to the clinic.
In addition to mutations/deletions that disrupt the RB1 gene, the encoded protein, pRb, is often inactivated in cancer by phosphorylation induced by cyclin-dependent kinases. To study the effect of pRb phosphorylation in vivo, we created mutant mice in which key Ser/Thr phospho-acceptor sites are substituted to Ala residues by homologous re-combination. Analysis of these phospho-mutant Rb knock-in mice has uncovered unanticipated roles for this tumor suppressor in homeostasis of specific tissues. Using these mice, we are studying the effect of unphosphorylatable pRb on cancer progression and aging.