Topoisomerase 2 Beta Is Expressed in Primary and Metastatic Prostate Adenocarcinoma
MC Haffner, L Schultz, AM De Marzo, WG Nelson, S Yegnasubramanian, GJ Netto. Johns Hopkins University, Baltimore, MD
Background: Recent evidence suggests that Topoisomerase 2 beta (TOP2β) is involved in androgen receptor (AR) signaling and is required for efficient AR-mediated transcriptional initiation. TOP2β could therefore represent a novel target to modulate androgen signaling in prostate cancer (PCa). Thus far however, no data exist on the expression pattern of TOP2β in different stages of PCa progression.
Design: Tissue microarrays (TMA) were constructed from archival formalin fixed paraffin embedded tissue from 31 primary PCa (2000-2001) and unrelated 66 metastatic tumors treated in our institution (1992-2001). The mean representation for each tumor was 2.4 spots. Standard immunohistochemistry was performed using TOP2β (Bethyl Laboratories, Montgomery, TX) specific atibody. Specificity was confirmed by siRNA mediated knockdown experiments by immunohistochemical staining and western blotting. Each TMA spot was individually assigned a Gleason score. Nuclear and cytoplasmic expression was assigned a extent (percentage of positive cells) for each category of intensity level (0 to 3+). A final H-score was obtained for each spot as the sum of intensity x extent products and was later correlated with pathologic characteristics.
Results: All 97 cases (100%) expressed TOP2β. We observed positive staining for TOP2β in 68/72 spots (94%) of primary PCa and 149/154 (97%) metastatic PCa. Staining was predominantly localized to the nucleus with moderate to strong intensity. A weak to moderate coexistent cytoplasmic staining was seen in the majority of cases. We observed a significant negative correlation between Gleason sum and TOP2β expression scores (r = - 0.332, P = 0.004) indicating that lower Gleason grade tumors (Gleason sum <7) show higher TOP2β expression.
Conclusions: Our study is the first to document TOP2β expression in primary and metastatic PCa and therefore validates TOP2β as a potential drug target in prostate cancer. Furthermore we show an inverse relationship between TOP2β expression and Gleason score suggesting that high levels of TOP2β are associated with a more differentiated phenotype.
Category: Genitourinary (including renal tumors)
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 117, Wednesday Afternoon