title: Notch1 phenotype and clinical stage progression in non-small cell lung cancer.
abstract: BACKGROUND
  Notch1 transmembrane receptor is activated through ligand-binding- triggered proteolytic cleavages and, upon release, the intracellular domain (N1-ICD) translocates into the nucleus and modulates target gene transcriptions. Notch activation has been implicated in tumorigenesis in an increasing number of human malignancies including non-small cell lung cancer (NSCLC). However, Notch1 in distinct expression patterns and activation status with tumor progression remains to be defined in NSCLC.
  
  
  METHODS
  Notch1 and activated Notch1, N1-ICD, were examined by immunohistochemistry in 58 cases of stage I to IV NSCLC tumors. Association between Notch1 or N1-ICD expression and clinicopathological factors was assessed via correlation coefficient r statistics. P-values are two-sided.
  
  
  RESULTS
  Detectable tumor Notch1, predominantly localized to the membrane and cytoplasm, was observed in 29 cases (50%, 95% Blyth-Still-Casella confidence interval 37 - 63%). It was negatively associated with stage (r=- 0.43, P<0.001) and nodal status (r=- 0.33, P = 0.01), but not tumor size. In contrast, nuclear N1-ICD expression level was low and found in 12% of NSCLC patients, neither significantly associated with stage nor nodal status. Upon Notch1 activation in vitro, a mostly extra-nuclear staining was substantially turned into the nuclear signal in cancer cells.
  
  
  CONCLUSIONS
  Notch1 in the largely inactivated phenotype is inversely associated with clinical stage progression in NSCLC. Notch1, rather than activated N1-ICD, may be a context-dependent restrictive factor to nodal metastasis.
authors: National Clinical Target Validation Laboratory, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. nguyend@navmed.nci.nih.gov.
authors: Dat
authors: D
authors: Nguyen
authors: Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. rubinsteinl@ctep.nci.nih.gov.
authors: Larry
authors: L
authors: Rubinstein
authors: Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. takeben@mail.nih.gov.
authors: Naoko
authors: N
authors: Takebe
authors: Stanley Scott Cancer Center, Louisiana State University Health Sciences Center and Louisiana Cancer Research Consortium, New Orleans, LA, USA. lmiele@lsuhsc.edu.
authors: Lucio
authors: L
authors: Miele
authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. tomaszewsk@dtpepn.nci.nih.gov.
authors: Joseph E
authors: JE
authors: Tomaszewski
authors: Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. ivyp@ctep.nci.nih.gov.
authors: Percy
authors: P
authors: Ivy
authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. doroshoj@mail.nih.gov.
authors: James H
authors: JH
authors: Doroshow
authors: National Clinical Target Validation Laboratory, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. Sherry.Yang@nih.gov.
authors: Sherry X
authors: SX
authors: Yang
mesh_terms: D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D051881:Receptor, Notch1 / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1
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