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Molecular Biology, Pathobiology, and Genetics |
1 Divisions of Hematology and Medical Oncology, 2 Allergy/Pulmonary and Critical Care Medicine, and 3 Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee
Requests for reprints: Thao P. Dang, Division of Hematology and Medical Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 642 PRB, Nashville, TN 37232. Phone: 615-936-3942; Fax: 615-936-1601; E-mail: thao.p.dang{at}vanderbilt.edu.
Notch3 is a member of an evolutionarily conserved family of cell surface receptors important in cell-fate determination in both vertebrates and invertebrates. Significant data support the role of Notch pathway in cancer development, although the conflicting role of Notch signaling pathways in tumorigenesis suggests that its action is highly context-dependent. Furthermore, although Notch receptors signal primarily through the regulation of hairy enhancer of split (HES) and HES-related (HRT) genes, they are known to crosstalk with other signaling pathways, including the epidermal growth factor (EGF) and the mitogen-activated protein kinase pathways. Whereas much is known about the role of Notch1 in human cancer, the role of Notch3 in epithelial tumors, such as lung carcinomas, has not been well established. In this study, we show that Notch3 is expressed in 80 of 207 (39%) resected human lung tumors and that its expression is positively correlated with EGF receptor expression. Inhibition of the Notch3 pathway using a dominant-negative receptor dramatically reduces growth in soft agar and increases growth factor dependence. We also find that Notch inhibition increases sensitivity to EGF receptor tyrosine kinase inhibition and decrease in phosphorylation of the mitogen-activated protein kinase. These observations support a role for Notch3 signaling in lung cancer, and one potential mechanism of maintaining the neoplastic phenotype is through the modulation of the EGF pathway.
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 B. W. Purow, T. K. Sundaresan, M. J. Burdick, B. A. Kefas, L. D. Comeau, M. P. Hawkinson, Q. Su, Y. Kotliarov, J. Lee, W. Zhang, et al. Notch-1 regulates transcription of the epidermal growth factor receptor through p53 Carcinogenesis, May 1, 2008; 29(5): 918 - 925. [Abstract] [Full Text] [PDF]
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K. Li, Y. Li, W. Wu, W. R. Gordon, D. W. Chang, M. Lu, S. Scoggin, T. Fu, L. Vien, G. Histen, et al. Modulation of Notch Signaling by Antibodies Specific for the Extracellular Negative Regulatory Region of NOTCH3 J. Biol. Chem., March 21, 2008; 283(12): 8046 - 8054. [Abstract] [Full Text] [PDF]
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Y. Chen, M. A. De Marco, I. Graziani, A. F. Gazdar, P. R. Strack, L. Miele, and M. Bocchetta Oxygen Concentration Determines the Biological Effects of NOTCH-1 Signaling in Adenocarcinoma of the Lung Cancer Res., September 1, 2007; 67(17): 7954 - 7959. [Abstract] [Full Text] [PDF]
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J. Konishi, K. S. Kawaguchi, H. Vo, N. Haruki, A. Gonzalez, D. P. Carbone, and T. P. Dang {gamma}-Secretase Inhibitor Prevents Notch3 Activation and Reduces Proliferation in Human Lung Cancers Cancer Res., September 1, 2007; 67(17): 8051 - 8057. [Abstract] [Full Text] [PDF]
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 J. O'Neil, J. Grim, P. Strack, S. Rao, D. Tibbitts, C. Winter, J. Hardwick, M. Welcker, J. P. Meijerink, R. Pieters, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to {gamma}-secretase inhibitors J. Exp. Med., August 6, 2007; 204(8): 1813 - 1824. [Abstract] [Full Text] [PDF]
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 E. Fung, S.-M. T. Tang, J. P. Canner, K. Morishige, J. F. Arboleda-Velasquez, A. A. Cardoso, N. Carlesso, J. C. Aster, and M. Aikawa Delta-Like 4 Induces Notch Signaling in Macrophages: Implications for Inflammation Circulation, June 12, 2007; 115(23): 2948 - 2956. [Abstract] [Full Text] [PDF]
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 V. Dasari, M. Gallup, H. Lemjabbar, I. Maltseva, and N. McNamara Epithelial-Mesenchymal Transition in Lung Cancer: Is Tobacco the "Smoking Gun"? Am. J. Respir. Cell Mol. Biol., July 1, 2006; 35(1): 3 - 9. [Full Text] [PDF]
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 L. Miele Notch Signaling Clin. Cancer Res., February 15, 2006; 12(4): 1074 - 1079. [Full Text] [PDF]
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 M. V. Sundaram The love-hate relationship between Ras and Notch Genes & Dev., August 15, 2005; 19(16): 1825 - 1839. [Abstract] [Full Text] [PDF]
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