title: Notch3 and HEY-1 as prognostic biomarkers in pancreatic adenocarcinoma.
abstract: In order to achieve a better outcome for pancreatic cancer patients, reliable biomarkers are required which allow for improved diagnosis. These may emanate from a more detailed molecular understanding of the aggressive nature of this disease. Having previously reported that Notch3 activation appeared to be associated with more aggressive disease, we have now examined components of this pathway (Notch1, Notch3, Notch4, HES-1, HEY-1) in more detail in resectable (n = 42) and non-resectable (n = 50) tumours compared to uninvolved pancreas. All three Notch family members were significantly elevated in tumour tissue, compared to uninvolved pancreas, with expression maintained within matched lymph node metastases. Furthermore, significantly higher nuclear expression of Notch1, -3 and -4, HES-1, and HEY-1 (all p ≤ 0.001) was noted in locally advanced and metastatic tumours compared to resectable cancers. In survival analyses, nuclear Notch3 and HEY-1 expression were significantly associated with reduced overall and disease-free survival following tumour resection with curative intent, with nuclear HEY-1 maintaining independent prognostic significance for both outcomes on multivariate analysis. These data further support a central role for Notch signalling in pancreatic cancer and suggest that nuclear expression of Notch3 and its target gene, HEY-1, merit validation in biomarker panels for diagnosis, prognosis and treatment efficacy. A peptide fragment of Notch3 was detected in plasma from patients with inoperable pancreatic cancer, but due to wide inter-individual variation, mean levels were not significantly different compared to age-matched controls.
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, Leicestershire, United Kingdom.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Mann
authors.forename: Christopher
authors.initials: C
authors.lastname: Bastianpillai
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Neal
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Masood
authors.forename: Donald J L
authors.initials: DJ
authors.lastname: Jones
authors.forename: Friederike
authors.initials: F
authors.lastname: Teichert
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.forename: Elena
authors.initials: E
authors.lastname: Karpova
authors.forename: David P
authors.initials: DP
authors.lastname: Berry
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Manson
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D010455:Peptides / Q000097:blood / Q000737:chemistry; D011379:Prognosis; D016016:Proportional Hazards Models; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000097:blood / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D010455:Peptides; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C485631:HEY1 protein, human; C499374:NOTCH3 protein, human