Expression of the Notch Family of Proteins in Prostatic Adenocarcinomas (PACs): Notch2 Signaling Is Associated with High Tumor Grade, Advanced Stage and Biochemical Disease Recurrence
BVS Kallakury, GM Sheehan, CE Sheehan, JS Ross. Georgetown University Hospital, Washington, DC; Albany Medical College, Albany, NY
Background: Notch signaling is associated with cell differentiation and proliferation in experimental cancer models. Aberrant Notch signaling has been documented in prostate cancer xenografts. However, the prognostic significance of Notch signaling in human PACs has not been elucidated.
Design: Formalin-fixed, paraffin embedded sections from 143 PACs were immunostained by automated methods (Ventana) with antibodies to Notch1, Notch2, Notch3 and Notch4 (Santa Cruz). Cytoplasmic immunoreactivity for each protein was scored based on intensity and percentage positive cells in both tumor and adjacent benign epithelium. A multiplicative index was calculated and cases assessed as tumor=benign (T=B), tumor>benign (T>B) and tumor<benign (T<B). Results were correlated with clinicopathologic variables.
Results: Variable cytoplasmic immunoreactivity was noted in adjacent benign glands for all 4 Notch proteins in all cases. Tumor immunoreactivity was predominantly cytoplasmic for all 4 proteins, while rare nuclear positivity was observed for Notch1 and Notch4. Notch protein expression was noted as: Notch1 [T=B 88%, T>B 11%, T<B 1%]; Notch2 [T=B 24%, T>B 76%]; Notch3 [T=B 13%, T>B 87%]; Notch 4 [T=B 38%, T>B 57%, T<B 5%]. Increased Notch1 expression correlated with high grade [16% HG vs 7% LG, p=0.05]; while nuclear expression was noted in 8 cases and correlated with HG [13% HG vs 0% LG, p=0.001]. Increased Notch2 expression correlated with HG [90% HG vs 67% LG, p=0.001], advanced stage [86% advanced vs 67% early, p=0.014], and biochemical disease recurrence [87% recur vs 68% non-recur, p=0.008]. While Notch3 immunoreactivity was increased in a majority of cases and basal cell expression was observed, there were no significant correlations. Overall Notch4 dysregulation [T>B + T<B] correlated with HG (p=0.028); while nuclear expression was noted in 5 cases and correlated with advanced stage (p=0.026). On multivariate analysis, advanced stage (p=0.001) and increased Notch2 expression (p=0.05) independently predicted biochemical disease recurrence.
Conclusions: Aberrant Notch signaling is associated with disease aggressiveness in PAC with Notch2 overexpression independently predicting disease recurrence. Further study of Notch protein expression in PAC as prognostic factors and targets of therapy appears warranted.
Category: Genitourinary (including renal tumors)
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 94, Wednesday Morning