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Overexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia.
Cancer Res 2001; 61(24):8830-7CR

Abstract

Pancreatic cancer (PC) is thought to develop through a series of duct lesions termed pancreatic intraepithelial neoplasia (PanIN). Characterization of the molecular pathology of these lesions may lead to additional understanding of pancreatic ductal carcinogenesis. We examined the protein expression of four functionally related genes, p21(WAF1/CIP1) (CDKN1A), p53, cyclin D1 (CCND1), and DPC4/Smad4 (MADH4), aberrations of which are associated with PC, within 451 PanIN lesions present in the pancreata of 60 patients. p21(WAF1/CIP1) overexpression was present in the normal ducts of 9% of patients and increased progressively to 16% of patients with PanIN-1A lesions, to 32% of patients with PanIN-1B lesions, 56% of patients with PanIN-2 lesions, 80% of patients with PanIN-3 lesions, and 85% of patients with invasive carcinomas (P < 0.01). p53 and cyclin D1 overexpression occurred predominantly in PanIN-3 lesions (P < 0.01), and loss of DPC4/Smad4 expression occurred predominantly in PanIN-3 lesions and invasive carcinoma (P < 0.01). In addition, p21(WAF1/CIP1) overexpression occurred independently of p53 and DPC4/Smad4 expression within invasive carcinoma and PanIN-3 lesions. Cyclin D1 overexpression or loss of DPC4/Smad4 expression was apparent in 85% of invasive carcinomas but in only 14% of PanIN-2 lesions. These data demonstrate that overexpression of p21(WAF1/CIP1) occurs early in the development of PanIN, before aberrations in p53, cyclin D1, and DPC4/Smad4 expression. p21(WAF1/CIP1) overexpression, independent of p53 and/or DPC4/Smad4 expression, may reflect increased Ras activity, either directly through activating K-ras mutations or as a consequence of HER-2/neu (ERBB2) overexpression, both of which are common in PC and in early events in the development of PanIN. These data support further the current progression model for PC and demonstrate that aberrant expression of key cell cycle regulatory genes may be important in the early development and progression of PanIN.

Authors+Show Affiliations

Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, NSW 2010 Australia.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11751405

Citation

Biankin, A V., et al. "Overexpression of p21(WAF1/CIP1) Is an Early Event in the Development of Pancreatic Intraepithelial Neoplasia." Cancer Research, vol. 61, no. 24, 2001, pp. 8830-7.
Biankin AV, Kench JG, Morey AL, et al. Overexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia. Cancer Res. 2001;61(24):8830-7.
Biankin, A. V., Kench, J. G., Morey, A. L., Lee, C. S., Biankin, S. A., Head, D. R., ... Sutherland, R. L. (2001). Overexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia. Cancer Research, 61(24), pp. 8830-7.
Biankin AV, et al. Overexpression of p21(WAF1/CIP1) Is an Early Event in the Development of Pancreatic Intraepithelial Neoplasia. Cancer Res. 2001 Dec 15;61(24):8830-7. PubMed PMID: 11751405.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia. AU - Biankin,A V, AU - Kench,J G, AU - Morey,A L, AU - Lee,C S, AU - Biankin,S A, AU - Head,D R, AU - Hugh,T B, AU - Henshall,S M, AU - Sutherland,R L, PY - 2001/12/26/pubmed PY - 2002/1/11/medline PY - 2001/12/26/entrez SP - 8830 EP - 7 JF - Cancer research JO - Cancer Res. VL - 61 IS - 24 N2 - Pancreatic cancer (PC) is thought to develop through a series of duct lesions termed pancreatic intraepithelial neoplasia (PanIN). Characterization of the molecular pathology of these lesions may lead to additional understanding of pancreatic ductal carcinogenesis. We examined the protein expression of four functionally related genes, p21(WAF1/CIP1) (CDKN1A), p53, cyclin D1 (CCND1), and DPC4/Smad4 (MADH4), aberrations of which are associated with PC, within 451 PanIN lesions present in the pancreata of 60 patients. p21(WAF1/CIP1) overexpression was present in the normal ducts of 9% of patients and increased progressively to 16% of patients with PanIN-1A lesions, to 32% of patients with PanIN-1B lesions, 56% of patients with PanIN-2 lesions, 80% of patients with PanIN-3 lesions, and 85% of patients with invasive carcinomas (P < 0.01). p53 and cyclin D1 overexpression occurred predominantly in PanIN-3 lesions (P < 0.01), and loss of DPC4/Smad4 expression occurred predominantly in PanIN-3 lesions and invasive carcinoma (P < 0.01). In addition, p21(WAF1/CIP1) overexpression occurred independently of p53 and DPC4/Smad4 expression within invasive carcinoma and PanIN-3 lesions. Cyclin D1 overexpression or loss of DPC4/Smad4 expression was apparent in 85% of invasive carcinomas but in only 14% of PanIN-2 lesions. These data demonstrate that overexpression of p21(WAF1/CIP1) occurs early in the development of PanIN, before aberrations in p53, cyclin D1, and DPC4/Smad4 expression. p21(WAF1/CIP1) overexpression, independent of p53 and/or DPC4/Smad4 expression, may reflect increased Ras activity, either directly through activating K-ras mutations or as a consequence of HER-2/neu (ERBB2) overexpression, both of which are common in PC and in early events in the development of PanIN. These data support further the current progression model for PC and demonstrate that aberrant expression of key cell cycle regulatory genes may be important in the early development and progression of PanIN. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/11751405/Overexpression_of_p21_WAF1/CIP1__is_an_early_event_in_the_development_of_pancreatic_intraepithelial_neoplasia_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=11751405 DB - PRIME DP - Unbound Medicine ER -