Assessment of the p27/Skp2/Cks1 Axis in Pancreatic Ductal Adenocarcinoma and Ampullary Adenocarcinoma
AM Bellizzi, M Bloomston, SM Bellizzi, OH Iwenofu, WL Frankel. Ohio State University, Columbus, OH
Background: p27, a tumor suppressor, is a cyclin dependent kinase inhibitor governing cell cycle progression. Skp2 and Cks1 are components of an E3-ubiquitin ligase responsible for p27's ubiquitylation and subsequent proteosomal degradation. These proteins direct p27 recognition and binding, conferring specificity to the E3-complex. Loss of p27 and overexpression of Skp2 and Cks1 have been described in various tumors. We investigated this pathway because these proteins have rarely been studied in pancreatic ductal adenocarcinoma (PDA), and, to our knowledge, they have not been studied in ampullary adenocarcinoma (AMP).
Design: Tissue microarrays were constructed from cases of PDA (67), AMP (40), and non-neoplastic ducts (NML, 35); duplicate cores were taken from each case. Immunohistochemistry for p27, Skp2, and Cks1 was performed. p27 and Skp2 were scored as follows: p27 (positive:10% nuclear staining), Skp2 (positive:5% nuclear staining). Cks1 was evaluated for intensity (0, 1+, 2+) and quantity (%) of nuclear staining and a score (product of intensity and quantity) was calculated. Fisher's exact test (p27 and Skp2) and Mann Whitney U test (Cks1) were used for pairwise comparisons. Log-rank analysis (p27 and Skp2) and Cox proportional hazards model (Cks1) were used for survival analysis.
Results: Loss of p27 expression was noted in just over half of PDAs and AMPs, while Skp2 and Cks1 were frequently overexpressed (see table). Comparisons between PDA vs. NML and AMP vs. NML were highly statistically significant for all 3 proteins (p0.001). While Skp2 and Cks1 expression correlated with survival in PDA (p=0.02, 0.03), they did not in AMP. p27 failed to correlate with survival in PDA or AMP.
Expression of p27, Skp2, and Cks1for p27 and Skp2 data represents number of positive/total cases; Cks1 reported as score sd
|p27||28/65 (43%)||29/33 (88%)||18/40 (45%)|
|Skp2||31/66 (47%)||0/35 (0%)||26/37 (70%)|
|Cks1||46.7 45.4||5.7 11.5||81.3 61.8|
Conclusions: p27 expression is commonly decreased, while Skp2 and Cks1 expression is frequently increased in PDA and AMP. Skp2 and Cks1 correlate with survival in PDA and not in AMP. Lack of correlation in AMP may reflect the relatively indolent nature of these tumors. Given their frequent overexpression in PDA and AMP and their limited target specificities, Skp2 and Cks1 represent potential targets for small molecule therapy. They also may be potential prognostic indicators.
Category: Liver & Pancreas
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 204, Monday Morning