Notch Signaling Pathway as a Therapeutic Target in Breast Cancer

The highly conserved Notch signaling pathway is involved in regulating a number of key cellular processes. This pathway has been implicated in both the development and progression of breast cancer and has emerged as a possible therapeutic target. Several clinical trials are currently underway to determine if targeting the Notch pathway with drugs such as the γ-secretase inhibitors may be an effective therapeutic strategy that improves outcomes in this disease. Mol Cancer Ther; 10(1); 9–15. ©2010 AACR.

[1]  Sathish Kumar Mungamuri,et al.  Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. , 2006, Cancer research.

[2]  F. Oswald,et al.  NF-κB2 Is a Putative Target Gene of Activated Notch-1 via RBP-Jκ , 1998, Molecular and Cellular Biology.

[3]  L. Miele,et al.  NOTCH signaling as a novel cancer therapeutic target. , 2006, Current cancer drug targets.

[4]  M. Fortini,et al.  Notch: Neurogenesis is only part of the picture , 1993, Cell.

[5]  D. Carvajal,et al.  Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. , 2009, Cancer research.

[6]  Christopher C W Hughes,et al.  Notch activation during endothelial cell network formation in vitro targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR expression. , 2002, Microvascular research.

[7]  N. Patel,et al.  Inhibition of angiogenesis and tumor growth by and ?-secretase inhibitors , 2005 .

[8]  Yang Wang,et al.  Fringe is a glycosyltransferase that modifies Notch , 2000, Nature.

[9]  S. Artavanis-Tsakonas,et al.  Alterations in Notch signaling in neoplastic lesions of the human cervix. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[10]  A. Goate,et al.  A common enzyme connects notch signaling and Alzheimer's disease. , 2000, Genes & development.

[11]  Min-Zu Wu,et al.  The CBF1-independent Notch1 signal pathway activates human c-myc expression partially via transcription factor YY1. , 2007, Carcinogenesis.

[12]  G. Dontu,et al.  Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells , 2004, Breast Cancer Research.

[13]  Andrew P. Weng,et al.  Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia , 2004, Science.

[14]  J. Aster,et al.  Multiple niches for Notch in cancer: context is everything. , 2004, Current opinion in genetics & development.

[15]  Patrick Maisonneuve,et al.  Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis , 2004, The Journal of cell biology.

[16]  Gavin Thurston,et al.  Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis , 2006, Nature.

[17]  P. Leder,et al.  Ras pathway signals are required for notch-mediated oncogenesis , 2000, Oncogene.

[18]  W. Hahn,et al.  Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells , 2002, Nature Medicine.

[19]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[20]  A. Capobianco,et al.  Induction of Cyclin D1 Transcription and CDK2 Activity by Notchic: Implication for Cell Cycle Disruption in Transformation by Notchic , 2001, Molecular and Cellular Biology.

[21]  Tian-Li Wang,et al.  Notch3 gene amplification in ovarian cancer. , 2006, Cancer research.

[22]  Deepa Subramanyam,et al.  Cooperation of Notch and Ras/MAPK signaling pathways in human breast carcinogenesis , 2009, Molecular Cancer.

[23]  Chindo Hicks,et al.  Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches. , 2008, Cancer research.

[24]  B. Osborne,et al.  Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents , 2003, Oncogene.

[25]  Shinya Watanabe,et al.  NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells. , 2008, Cancer research.

[26]  Guido Nikkhah,et al.  NOTCH Pathway Blockade Depletes CD133‐Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts , 2009, Stem cells.

[27]  T. Golde,et al.  Rational targeting of Notch signaling in cancer , 2008, Oncogene.

[28]  Eric C. Lai,et al.  Notch signaling: control of cell communication and cell fate , 2004, Development.

[29]  W. Zuercher,et al.  Evidence for Allosteric Interactions of Antagonist Binding to the Smoothened Receptor , 2009, Journal of Pharmacology and Experimental Therapeutics.

[30]  Thijs J. Hagenbeek,et al.  Therapeutic antibody targeting of individual Notch receptors , 2010, Nature.

[31]  Timothy Harrison,et al.  Apoptosis in T cell acute lymphoblastic leukemia cells after cell cycle arrest induced by pharmacological inhibition of notch signaling. , 2007, Chemistry & biology.

[32]  R. Callahan,et al.  Identification of a novel NOTCH-4/INT-3 RNA species encoding an activated gene product in certain human tumor cell lines , 2000, Oncogene.

[33]  N. Patel,et al.  Inhibition of angiogenesis and tumor growth by beta and gamma-secretase inhibitors. , 2005, European journal of pharmacology.

[34]  B. Weinstein,et al.  sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. , 2002, Developmental cell.

[35]  S. Bull,et al.  Expression profiling of familial breast cancers demonstrates higher expression of FGFR2 in BRCA2-associated tumors , 2008, Breast Cancer Research and Treatment.

[36]  C. Stewart,et al.  Determination of the gamma-secretase inhibitor MK-0752 in human plasma by online extraction and electrospray tandem mass spectrometry (HTLC-ESI-MS/MS). , 2010, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[37]  T. Sun,et al.  Identification of a Family of Mastermind-Like Transcriptional Coactivators for Mammalian Notch Receptors , 2002, Molecular and Cellular Biology.

[38]  C. Hsieh,et al.  A functional Notch–survivin gene signature in basal breast cancer , 2008, Breast Cancer Research.

[39]  J. Hsieh,et al.  SKIP, a CBF1-Associated Protein, Interacts with the Ankyrin Repeat Domain of NotchIC To Facilitate NotchIC Function , 2000, Molecular and Cellular Biology.

[40]  T. Yeatman,et al.  Downregulation of Notch pathway by a gamma-secretase inhibitor attenuates AKT/mammalian target of rapamycin signaling and glucose uptake in an ERBB2 transgenic breast cancer model. , 2010, Cancer research.

[41]  Jan Kitajewski,et al.  Notch regulates the angiogenic response via induction of VEGFR-1 , 2010, Journal of angiogenesis research.

[42]  R. Coombes,et al.  Inhibition of γ-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells , 2009, British Journal of Cancer.

[43]  J. Dick,et al.  Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell , 1997, Nature Medicine.

[44]  G. Dontu,et al.  Mammary stem cells, self-renewal pathways, and carcinogenesis , 2005, Breast Cancer Research.

[45]  E. Winer,et al.  Phase I pharmacokinetic (PK), and pharmacodynamic (PD) trial of the novel oral Notch inhibitor MK-0752 in patients (pts) with advanced breast cancer (BC) and other solid tumors. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[46]  D. Santini,et al.  IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. , 2007, The Journal of clinical investigation.

[47]  D. Hedley,et al.  Raf kinase as a target for anticancer therapeutics , 2005, Molecular Cancer Therapeutics.

[48]  Wolfgang H. Fischer,et al.  Regulation of the ERBB-2 Promoter by RBPJκ and NOTCH* , 1997, The Journal of Biological Chemistry.

[49]  N. Anderson,et al.  Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways. , 2007, Journal of the National Cancer Institute.

[50]  A. Harris,et al.  Up-Regulation of Endothelial Delta-like 4 Expression Correlates with Vessel Maturation in Bladder Cancer , 2006, Clinical Cancer Research.

[51]  Kenji Matsuno,et al.  Notch signaling. , 1995, Science.

[52]  S. Pongor,et al.  The intracellular region of Notch ligands: does the tail make the difference? , 2007, Biology Direct.

[53]  Raphael Kopan,et al.  Notch: a membrane-bound transcription factor. , 2002, Journal of cell science.

[54]  M. Hendrix,et al.  Notch and NOXA-related pathways in melanoma cells. , 2005, The journal of investigative dermatology. Symposium proceedings.

[55]  S. Morrison,et al.  Prospective identification of tumorigenic breast cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[56]  T. Giordano,et al.  Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. , 2005, Cancer cell.

[57]  R. Clarke,et al.  Aberrant Activation of Notch Signaling in Human Breast Cancer , 2006 .

[58]  T. Golde,et al.  ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a γ-secretase inhibitor , 2008, Oncogene.

[59]  G. Lockwood,et al.  High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. , 2005, Cancer research.

[60]  Cynthia Hawkins,et al.  Identification of a cancer stem cell in human brain tumors. , 2003, Cancer research.

[61]  Zhiwei Wang,et al.  Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells , 2006, Molecular Cancer Therapeutics.

[62]  J. Aster,et al.  c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. , 2006, Genes & development.

[63]  J. Sklar,et al.  TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms , 1991, Cell.

[64]  C. Leow,et al.  Notch receptors, partners and regulators: from conserved domains to powerful functions. , 1998, Current topics in microbiology and immunology.

[65]  A. Diévart,et al.  Involvement of Notch1 in the development of mouse mammary tumors , 1999, Oncogene.

[66]  D. Santini,et al.  p66Shc/Notch‐3 Interplay Controls Self‐Renewal and Hypoxia Survival in Human Stem/Progenitor Cells of the Mammary Gland Expanded In Vitro as Mammospheres , 2007, Stem cells.

[67]  J Silvio Gutkind,et al.  Distinct pattern of expression of differentiation and growth-related genes in squamous cell carcinomas of the head and neck revealed by the use of laser capture microdissection and cDNA arrays , 2000, Oncogene.

[68]  K. Raj,et al.  The role of Notch in tumorigenesis: oncogene or tumour suppressor? , 2003, Nature Reviews Cancer.

[69]  D. Gallahan,et al.  The mouse mammary tumor associated gene INT3 is a unique member of the NOTCH gene family (NOTCH4) , 1997, Oncogene.

[70]  G. Lockwood,et al.  High-level JAG1 mRNA and protein predict poor outcome in breast cancer , 2007, Modern Pathology.

[71]  M. Muskavitch,et al.  Delta-notch signaling and Drosophila cell fate choice. , 1994, Developmental biology.

[72]  Hong Wang,et al.  Nicastrin Is Critical for Stability and Trafficking but Not Association of Other Presenilin/γ-Secretase Components* , 2005, Journal of Biological Chemistry.

[73]  J. Hsieh,et al.  Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2 , 1996, Molecular and cellular biology.

[74]  M. Skobe,et al.  Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. , 2007, The Journal of clinical investigation.

[75]  Anna Marie Mulligan,et al.  JAG1 expression is associated with a basal phenotype and recurrence in lymph node-negative breast cancer , 2008, Breast Cancer Research and Treatment.

[76]  W. Fischer,et al.  Regulation of the ERBB-2 promoter by RBPJkappa and NOTCH. , 1997, The Journal of biological chemistry.

[77]  Christel Brou,et al.  Signalling downstream of activated mammalian Notch , 1995, Nature.