DF/HCC Program Affiliation

Breast Cancer
Cancer Genetics

Research Abstract

Our work concerns the fundamental mechanisms of human epithelial tumorigenesis. We focus on the p53 gene family, members of which are among the most prominent genes in human cancer biology. The recent identification of two p53-related genes, p63 and p73, has provided new insight into the diverse functions of this gene family in development and cancer. In contrast to p53, p63 does not appear to be targeted for mutations in human cancer. On the contrary, a potential oncogenic role for p63 is supported by its genomic amplification and/or overexpression in a broad variety of epithelial tumors. We are currently using multiple approaches to understand the biochemical properties of the p63 protein, its interactions with p53 and p73, and its functional role in development and cancer. One gene to emerge from our efforts to identify new pathways regulated by p53 family members is REDD1, a member of a novel, phylogenetically conserved gene family. Multiple studies by our group and others have demonstrated that REDD1 functions as a negative regulator of the TOR (Target Of Rapamycin) kinase, by modulating the activity of the Tuberous Sclerosis tumor suppressor complex. These findings imply the existence of novel pathways connecting cellular stress responses to the control of cellular metabolism. Since most human tumors exhibit abnormalities of p53 and/or TOR signaling, it seems likely that dysregulation of REDD1 or its homologue REDD2 will contribute to tumorigenesis. We are currently using animal models, in vitro studies and biochemical approaches to understand the mechanisms of REDD1/2-mediated regulation. Our success in defining novel functional interactions within the p53 family provides new therapeutic possibilities for a variety of treatment-refractory malignancies. We are currently developing high-throughput approaches to identify specific therapeutic targets within the critical pathways we have uncovered. Through collaborations with academic and industry partners we seek to rapidly develop and test the new treatments that may emerge based on our basic science discoveries. Our ability to work at the interface of basic tumor biology and therapeutic application is strongly supported by the research and clinical infrastructure of the MGH Cancer Center.

Publications

• Leong CO, Vidnovic N, Deyoung MP, Sgroi D, Ellisen LW.The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers.J Clin Invest 2007 Apr 19.
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• Carroll DK, Carroll JS, Leong CO, Cheng F, Brown M, Mills AA, Brugge JS, Ellisen LW.p63 regulates an adhesion programme and cell survival in epithelial cells.Nat Cell Biol 2006 Jun;8(6):551-61.
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• Rocco JW, Leong CO, Kuperwasser N, DeYoung MP, Ellisen LW.p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis.Cancer Cell 2006 Jan;9(1):45-56.
  16413471
• Sofer A, Lei K, Johannessen CM, Ellisen LW.Regulation of mTOR and cell growth in response to energy stress by REDD1.Mol Cell Biol 2005 Jul;25(14):5834-45.
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