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Rational targeting of Notch signaling in cancer

Oncogene volume 27, pages 5124–5131 (2008)Cite this article

Abstract

Accumulating preclinical and clinical evidence supports a pro-oncogenic function for Notch signaling in several solid tumors, particularly but not exclusively in breast cancer. Notch inhibitory agents, such as γ-secretase inhibitors, are being investigated as candidate cancer therapeutic agents. Interest in therapeutic modulation of the Notch pathway has been increased by recent reports, indicating that its role is important in controlling the fate of putative ‘breast cancer stem cells’. However, as is the case for most targeted therapies, successful targeting of Notch signaling in cancer will require a considerable refinement of our understanding of the regulation of this pathway and its effects in both normal and cancer cells. Notch signaling has bidirectional ‘cross talk’ interaction with multiple other pathways that include candidate therapeutic targets. Understanding these interactions will greatly increase our ability to design rational combination regimens. To determine which patients are most likely to benefit from treatment with Notch inhibitors, it will be necessary to develop molecular tests to accurately measure pathway activity in specific tumors. Finally, mechanism-based toxicities will have to be addressed by a careful choice of therapeutic agents, combinations and regimens. This article summarizes the current state of the field, and briefly describes opportunities and challenges for Notch-targeted therapies in oncology.

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References

  • Allenspach EJ, Maillard I, Aster JC, Pear WS . (2002). Notch signaling in cancer. Cancer Biol Ther 1: 466–476.

    Article  Google Scholar 

  • Bash J, Zong WX, Banga S, Rivera A, Ballard DW, Ron Y et al. (1999). Rel/NF-kappaB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors. EMBO J 18: 2803–2811.

    Article  CAS  Google Scholar 

  • Bellavia D, Mecarozzi M, Campese AF, Grazioli P, Gulino A, Screpanti I . (2007). Notch and Ikaros: not only converging players in T cell leukemia. Cell Cycle 6: 2730–2734.

    Article  CAS  Google Scholar 

  • Berman JN, Look AT . (2007). Targeting transcription factors in acute leukemia in children. Curr Drug Targets 8: 727–737.

    Article  CAS  Google Scholar 

  • Beverly LJ, Capobianco AJ . (2003). Perturbation of Ikaros isoform selection by MLV integration is a cooperative event in Notch(IC)-induced T cell leukemogenesis. Cancer Cell 3: 551–564.

    Article  CAS  Google Scholar 

  • Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR et al. (2000). A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell 5: 207–216.

    Article  CAS  Google Scholar 

  • Chen Y, De Marco MA, Graziani I, Gazdar AF, Strack PR, Miele L et al. (2007). Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung. Cancer Res 67: 7954–7959.

    Article  CAS  Google Scholar 

  • Dallman MJ, Smith E, Benson RA, Lamb JR . (2005). Notch: control of lymphocyte differentiation in the periphery. Curr Opin Immunol 17: 259–266.

    Article  CAS  Google Scholar 

  • Deftos ML, He Y-W, Ojata EW, Bevan MJ . (1998). Correlating Notch signaling with thymocyte maturation. Immunity 9: 777–786.

    Article  CAS  Google Scholar 

  • Dickson BC, Mulligan AM, Zhang H, Lockwood G, O'Malley FP, Egan SE et al. (2007). High-level JAG1 mRNA and protein predict poor outcome in breast cancer. Mod Pathol 20: 685–693.

    Article  CAS  Google Scholar 

  • Fan X, Mikolaenko I, Elhassan I, Ni X, Wang Y, Ball D et al. (2004). Notch1 and Notch2 have opposite effects on embryonal brain tumor growth. Cancer Res 64: 7787–7793.

    Article  CAS  Google Scholar 

  • Farnie G, Brennan K, Clarke RB, Bundred NJ . (2005). Ductal Carcinoma in situ (DCIS) mammosphere formation effect of epidermal growth factor (EGF) and Notch signaling pathways on self-renewal capacity. Breast Cancer Res Treat 94 (Suppl. 1): S14.

    Google Scholar 

  • Farnie G, Clarke RB . (2007). Mammary stem cells and breast cancer—role of Notch signalling. Stem Cell Rev 3: 169–175.

    Article  CAS  Google Scholar 

  • Farnie G, Clarke RB, Spence K, Pinnock N, Brennan K, Anderson NG et al. (2007). Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways. J Natl Cancer Inst 99: 616–627.

    Article  CAS  Google Scholar 

  • Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC . (2007). Structural basis for autoinhibition of Notch. Nat Struct Mol Biol 14: 295–300.

    Article  CAS  Google Scholar 

  • Gupta-Rossi N, Six E, LeBail O, Logeat F, Chastagner P, Olry A et al. (2004). Monoubiquitination and endocytosis direct gamma-secretase cleavage of activated Notch receptor. J Cell Biol 166: 73–83.

    Article  CAS  Google Scholar 

  • Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.

    Article  CAS  Google Scholar 

  • Houde C, Li Y, Song L, Barton K, Zhang Q, Godwin J et al. (2004). Over-expression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines. Blood 104: 3697–3704.

    Article  CAS  Google Scholar 

  • Jundt F, Anagnostopoulos I, Forster R, Mathas S, Stein H, Dorken B . (2002). Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood 99: 3398–3403.

    Article  CAS  Google Scholar 

  • Jundt F, Probsting KS, Anagnostopoulos I, Muehlinghaus G, Chatterjee M, Mathas S et al. (2004). Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. Blood 103: 3511–3515.

    Article  CAS  Google Scholar 

  • Kathrein KL, Chari S, Winandy S . (2008). Ikaros directly represses the Notch target gene Hes1 in a leukemia T cell line: implications for CD4 regulation. J Biol Chem 283: 10476–10484.

    Article  CAS  Google Scholar 

  • Koch U, Radtke F . (2007). Notch and cancer: a double-edged sword. Cell Mol Life Sci 64: 2746–2762.

    Article  CAS  Google Scholar 

  • Kopan R, Ilagan MX . (2004). Gamma-secretase: proteasome of the membrane? Nat Rev Mol Cell Biol 5: 499–504.

    Article  CAS  Google Scholar 

  • Kukar T, Golde TE . (2008). Possible mechanisms of action of NSAIDs and related compounds that modulate gamma-secretase cleavage. Curr Top Med Chem 8: 47–53.

    Article  CAS  Google Scholar 

  • Kwon C, Han Z, Olson EN, Srivastava D . (2005). MicroRNA1 influences cardiac differentiation in Drosophila and regulates Notch signaling. Proc Natl Acad Sci USA 102: 18986–18991.

    Article  CAS  Google Scholar 

  • Lai EC, Tam B, Rubin GM . (2005). Pervasive regulation of Drosophila Notch target genes by GY-box-, Brd-box-, and K-box-class microRNAs. Genes Dev 19: 1067–1080.

    Article  CAS  Google Scholar 

  • Li K, Li Y, Wu W, Gordon WR, Chang DW, Lu M et al. (2008). Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of Notch3. J Biol Chem 283: 8046–8054.

    Article  CAS  Google Scholar 

  • Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP et al. (2003). Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol 23: 14–25.

    Article  Google Scholar 

  • Malyukova A, Dohda T, von der LN, Akhondi S, Corcoran M, Heyman M et al. (2007). The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling. Cancer Res 67: 5611–5616.

    Article  CAS  Google Scholar 

  • McKenzie GJ, Khan M, Briend E, Stallwood Y, Champion BR . (2005). Notch: a unique therapeutic target for immunomodulation. Expert Opin Ther Targets 9: 395–410.

    Article  CAS  Google Scholar 

  • Miele L . (2006). Notch signaling. Clin Cancer Res 12: 1074–1079.

    Article  CAS  Google Scholar 

  • Miele L, Golde T, Osborne B . (2006). Notch signaling in cancer. Curr Mol Med 6: 905–918.

    Article  CAS  Google Scholar 

  • Minato Y, Yasutomo K . (2005). Regulation of acquired immune system by Notch signaling. Int J Hematol 82: 302–306.

    Article  CAS  Google Scholar 

  • Minter LM, Turley DM, Das P, Shin HM, Joshi I, Lawlor RG et al. (2005). Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Nat Immunol 6: 680–688.

    Article  CAS  Google Scholar 

  • Mukherjee A, Veraksa A, Bauer A, Rosse C, Camonis J, Artavanis-Tsakonas S . (2005). Regulation of Notch signalling by non-visual beta-arrestin. Nat Cell Biol 7: 1191–1201.

    Article  Google Scholar 

  • Nam Y, Sliz P, Pear WS, Aster JC, Blacklow SC . (2007). Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription. Proc Natl Acad Sci USA 104: 2103–2108.

    Article  CAS  Google Scholar 

  • Nam Y, Sliz P, Song L, Aster JC, Blacklow SC . (2006). Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell 124: 973–983.

    Article  CAS  Google Scholar 

  • Nickoloff BJ, Hendrix MJ, Pollock PM, Trent JM, Miele L, Qin JZ . (2005). Notch and NOXA-related pathways in melanoma cells. J Investig Dermatol Symp Proc 10: 95–104.

    Article  CAS  Google Scholar 

  • Nickoloff BJ, Qin JZ, Chaturvedi V, Denning MF, Bonish B, Miele L . (2002). Jagged-1 mediated activation of Notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma. Cell Death Differ 9: 842–855.

    Article  CAS  Google Scholar 

  • Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, Van Noort M et al. (2003). Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 33: 416–421.

    Article  CAS  Google Scholar 

  • Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW et al. (2007). Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Novartis Found Symp 283: 106–120.

    Article  CAS  Google Scholar 

  • O'neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C et al. (2007). FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to {gamma}-secretase inhibitors. J Exp Med 204: 1813–1824.

    Article  CAS  Google Scholar 

  • O'Neill CF, Urs S, Cinelli C, Lincoln A, Nadeau RJ, Leon R et al. (2007). Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth. Am J Pathol 171: 1023–1036.

    Article  CAS  Google Scholar 

  • Okajima T, Irvine KD . (2002). Regulation of Notch signaling by O-linked fucose. Cell 111: 893–904.

    Article  CAS  Google Scholar 

  • Osipo C, Golde TE, Osborne BA, Miele LA . (2008). Off the beaten pathway: the complex cross talk between Notch and NF-kappaB. Lab Invest 88: 11–17.

    Article  CAS  Google Scholar 

  • Oswald F, Kostezka U, Astrahantseff K, Bourteele S, Dillinger K, Zechner U et al. (2002). SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway. EMBO J 21: 5417–5426.

    Article  CAS  Google Scholar 

  • Oswald F, Winkler M, Cao Y, Astrahantseff K, Bourteele S, Knochel W et al. (2005). RBP-J{kappa}/SHARP recruits CtIP/CtBP corepressors to silence Notch target genes. Mol Cell Biol 25: 10379–10390.

    Article  CAS  Google Scholar 

  • Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M et al. (2007). Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 13: 1203–1210.

    Article  CAS  Google Scholar 

  • Parr C, Watkins G, Jiang WG . (2004). The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer. Int J Mol Med 14: 779–786.

    CAS  PubMed  Google Scholar 

  • Pece S, Serresi M, Santolini E, Capra M, Hulleman E, Galimberti V et al. (2004). Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol 167: 215–221.

    Article  CAS  Google Scholar 

  • Pinnix CC, Herlyn M . (2007). The many faces of Notch signaling in skin-derived cells. Pigment Cell Res 20: 458–465.

    Article  CAS  Google Scholar 

  • Pitsouli C, Delidakis C . (2005). The interplay between DSL proteins and ubiquitin ligases in Notch signaling. Development 132: 4041–4050.

    Article  CAS  Google Scholar 

  • Reedijk M, Odorcic S, Chang L, Zhang H, Miller N, McCready DR et al. (2005). High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res 65: 8530–8537.

    Article  CAS  Google Scholar 

  • Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y et al. (2006). Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444: 1083–1087.

    Article  CAS  Google Scholar 

  • Roy M, Pear WS, Aster JC . (2007). The multifaceted role of Notch in cancer. Curr Opin Genet Dev 17: 52–59.

    Article  CAS  Google Scholar 

  • Sansone P, Storci G, Giovannini C, Pandolfi S, Pianetti S, Taffurelli M et al. (2007). p66Shc/Notch-3 interplay controls self-renewal and hypoxia survival in human stem/progenitor cells of the mammary gland expanded in vitro as mammospheres. Stem Cells 25: 807–815.

    Article  CAS  Google Scholar 

  • Santolini E, Puri C, Salcini AE, Gagliani MC, Pelicci PG, Tacchetti C et al. (2000). Numb is an endocytic protein. J Cell Biol 151: 1345–1352.

    Article  CAS  Google Scholar 

  • Shih I, Wang TL . (2007). Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res 67: 1879–1882.

    Article  CAS  Google Scholar 

  • Song LL, Miele L . (2007). Cancer stem cells—an old idea that's new again: implications for the diagnosis and treatment of breast cancer. Expert Opin Biol Ther 7: 431–438.

    Article  CAS  Google Scholar 

  • Thompson BJ, Buonamici S, Sulis ML, Palomero T, Vilimas T, Basso G et al. (2007). The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J Exp Med 204: 1825–1835.

    Article  CAS  Google Scholar 

  • Thurston G, Noguera-Troise I, Yancopoulos GD . (2007). The delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nat Rev Cancer 7: 327–331.

    Article  CAS  Google Scholar 

  • Tu L, Fang TC, Artis D, Shestova O, Pross SE, Maillard I et al. (2005). Notch signaling is an important regulator of type 2 immunity. J Exp Med 202: 1037–1042.

    Article  CAS  Google Scholar 

  • Vilimas T, Mascarenhas J, Palomero T, Mandal M, Buonamici S, Meng F et al. (2007). Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat Med 13: 70–77.

    Article  CAS  Google Scholar 

  • Wang Y, Chan SL, Miele L, Yao PJ, Mackes J, Ingram DK et al. (2004). Involvement of Notch signaling in hippocampal synaptic plasticity. Proc Natl Acad Sci USA 101: 9458–9462.

    Article  CAS  Google Scholar 

  • Wang Z, Banerjee S, Li Y, Rahman KM, Zhang Y, Sarkar FH . (2006a). Down-regulation of Notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer Res 66: 2778–2784.

    Article  CAS  Google Scholar 

  • Wang Z, Zhang Y, Banerjee S, Li Y, Sarkar FH . (2006b). Inhibition of nuclear factor kappab activity by genistein is mediated via Notch-1 signaling pathway in pancreatic cancer cells. Int J Cancer 118: 1930–1936.

    Article  CAS  Google Scholar 

  • Weijzen S, Rizzo P, Braid M, Vaishnav R, Jonkheer SM, Zlobin A et al. (2002). Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med 8: 979–986.

    Article  CAS  Google Scholar 

  • Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T et al. (2004). Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279: 12876–12882.

    Article  CAS  Google Scholar 

  • Wu J, Bresnick EH . (2007). Glucocorticoid and growth factor synergism requirement for Notch4 chromatin domain activation. Mol Cell Biol 27: 2411–2422.

    Article  CAS  Google Scholar 

  • Wu J, Iwata F, Grass JA, Osborne CS, Elnitski L, Fraser P et al. (2005). Molecular determinants of NOTCH4 transcription in vascular endothelium. Mol Cell Biol 25: 1458–1474.

    Article  CAS  Google Scholar 

  • Yan M, Plowman GD . (2007). Delta-like 4/Notch signaling and its therapeutic implications. Clin Cancer Res 13: 7243–7246.

    Article  CAS  Google Scholar 

  • Yoo AS, Greenwald I . (2005). LIN-12/Notch activation leads to microRNA-mediated down-regulation of Vav in C. elegans. Science 310: 1330–1333.

    Article  CAS  Google Scholar 

  • Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H et al. (2005). Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 8: 13–23.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by NIH grant P01 AG2553101 and DOD IDEA grant W81XWH-04-1-0478. We are grateful to Antonio Pannuti for helpful discussions.

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Authors and Affiliations

  1. Breast Cancer Program, Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, IL, USA

    P Rizzo, C Osipo, K Foreman & L Miele

  2. Department of Neurology, Mayo Clinic at Jacksonville, Jacksonville, FL, USA

    T Golde

  3. Department of Veterinary and Animal Sciences, University of Massachusetts at Amherst, Amherst, MA, USA

    B Osborne

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  1. P Rizzo
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Correspondence to L Miele.

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Rizzo, P., Osipo, C., Foreman, K. et al. Rational targeting of Notch signaling in cancer. Oncogene 27, 5124–5131 (2008). https://doi.org/10.1038/onc.2008.226

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