UroToday - Prior analyses identified overexpression of the transcriptional repressor EZH2 as a significant predictor of poor outcome in organ-confined prostate cancer. Utilizing multiple data sources of cancer gene expression, the authors identify ADRB2 as a potential target of the Polycomb group protein complex PRC2 that includes EZH2. Data supporting this association was drawn from in vitro and in vivo studies and further supported by gene expression analyses of patient tumor samples.

The underexpression of ADRB2, associated in vivo with transcriptional repression through EZH2 overexpression, was associated with 5-fold increased invasion of benign prostate epithelial cells. Furthermore, DU145 prostate cancer cells in which EZH2 was knocked-down resulting in elevated ADRB2 did not form tumors in nude mice, while control DU145 cells grew as a xenograft. Similarly, DU145 prostate cancer xenografts grew significantly less when treated with the ADRB2 agonist isoproterenol when compared to vehicle treated controls (p=0.006).

The potential of ADRB2 as a biomarker of PCA aggressiveness was tested by immunohistochemistical analysis of 140 patient samples including benign, localized and metastatic tumor samples. The staining intensity was significantly lower in metastatic vs. localized vs. benign samples and suggested the ability of ADRB2 underexpression to predict poor outcomes in prostate cancer.

The clinical and pathological characteristics of 82 patients with organ-confined prostate cancer with 29 recurrence episodes were analyzed along with ADRB2 staining intensity. Low ADRB2 staining predicted biochemical recurrence independent of Gleason score, preoperative PSA, tumor diameter, and surgical margin status (p=0.002). When compared with the 5yr post-surgical Kattan nomogram, ADRB2 status provided independent and significant prediction of recurrence (p=0.015, RR =2.7, 95% CI 1.2-6.0).

In conclusion, this work highlights the potential of genetic or molecular biomarkers to stratify risk based on tumor specific biology in addition to histologic appearance. Furthermore, molecules that can promote or inhibit tumor growth are potential candidates for developing targeted therapies.



David S Morris, MD, Jindan Yu, MD, and Arul M Chinnaiyan, MD, as part of Beyond the Abstract on UroToday. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Link to Full Abstract

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