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.
  16715076
• 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.
  15988001
• Harvey KF, Mattila J, Sofer A, Bennett FC, Ramsey MR, Ellisen LW, Puig O, Hariharan IK.FOXO-regulated transcription restricts overgrowth of Tsc mutant organs.J Cell Biol 2008 Feb 25;180(4):691-6.
  18299344
• Li N, Singh S, Cherukuri P, Li H, Yuan Z, Ellisen LW, Wang B, Robbins D, Direnzo J.Reciprocal Intra-Epithelial Interactions between TP63 and Hedgehog Signaling Regulate Quiescence and Activation of Progenitor Elaboration by Mammary Stem Cells.Stem Cells 2
  18292212
• DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW.Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling.Genes Dev 2008 Jan 15;22(2):239-51.
  18198340
• Deyoung MP, Ellisen LW.p63 and p73 in human cancer: defining the network.Oncogene 2007 Aug 9;26(36):5169-83.
  17334395
• Wang H, Kubica N, Ellisen LW, Jefferson LS, Kimball SR.Dexamethasone represses signaling through the mammalian target of rapamycin in muscle cells by enhancing expression of REDD1.J Biol Chem 2006 Dec 22;281(51):39128-34.
  17074751
• Deyoung MP, Johannessen CM, Leong CO, Faquin W, Rocco JW, Ellisen LW.Tumor-Specific p73 Up-regulation Mediates p63 Dependence in Squamous Cell Carcinoma.Cancer Res 2006 Oct 1;66(19):9362-8.
  17018588
• Rocco JW, Ellisen LW.p63 and p73: life and death in squamous cell carcinoma.Cell Cycle 2006 May;5(9):936-40.
  16687923
• Ellisen LW.Growth Control Under Stress: mTOR Regulation through the REDD1-TSC Pathway.Cell Cycle 2005 Nov 1;4(11).
  16258273
• Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG.Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex.Genes Dev 2004 Dec 1;18(23):2893-904.
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• Burstein HJ, Harris LN, Gelman R, Lester SC, Nunes RA, Kaelin CM, Parker LM, Ellisen LW, Kuter I, Gadd MA, Christian RL, Kennedy PR, Borges VF, Bunnell CA, Younger J, Smith BL, Winer EP.Preoperative therapy with trastuzumab and paclitaxel followed by sequ
  12506169
• Ellisen LW, Ramsayer KD, Johannessen CM, Yang A, Beppu H, Minda K, Oliner JD, McKeon F, Haber DA.REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species.Mol Cell 2002 Nov;10(5):995-1005.
  12453409
• Ellisen LW.Regulation of gene expression by WT1 in development and tumorigenesis.Int J Hematol 2002 Aug;76(2):110-6.
  12215008
• Ellisen LW, Palmer RE, Maki RG, Truong VB, Tamayo P, Oliner JD, Haber DA.Cascades of transcriptional induction during human lymphocyte activation.Eur J Cell Biol 2001 May;80(5):321-8.
  11432721
• Ellisen LW, Carlesso N, Cheng T, Scadden DT, Haber DA.The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitor cells.EMBO J 2001 Apr 17;20(8):1897-909.
  11296223
• Wang W, Lee SB, Palmer R, Ellisen LW, Haber DA.A functional interaction with CBP contributes to transcriptional activation by the Wilms tumor suppressor WT1.J Biol Chem 2001 May 18;276(20):16810-6.
  11278547
• Harkin DP, Bean JM, Miklos D, Song YH, Truong VB, Englert C, Christians FC, Ellisen LW, Maheswaran S, Oliner JD, Haber DA.Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1.Cell 1999 May 28;97(5):575-86.
  10367887
• Kolquist KA, Ellisen LW, Counter CM, Meyerson M, Tan LK, Weinberg RA, Haber DA, Gerald WL.Expression of TERT in early premalignant lesions and a subset of cells in normal tissues.Nat Genet 1998 Jun;19(2):182-6.
  9620778
• Counter CM, Meyerson M, Eaton EN, Ellisen LW, Caddle SD, Haber DA, Weinberg RA.Telomerase activity is restored in human cells by ectopic expression of hTERT (hEST2), the catalytic subunit of telomerase.Oncogene 1998 Mar 5;16(9):1217-22.
  9528864
• Ellisen LW, Haber DA.Hereditary breast cancer.Annu Rev Med 1998;49:425-36.
  9509273
• Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA, Weinberg RA.hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during
  9288757
• Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J.TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.Cell 1991 Aug 23;66(4):649-61.
  1831692
• Weiss LM, Wood GS, Ellisen LW, Reynolds TC, Sklar J.Clonal T-cell populations in pityriasis lichenoides et varioliformis acuta (Mucha-Habermann disease).Am J Pathol 1987 Mar;126(3):417-21.
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