Distinct Patterns of Endothelin Axis Expression in Primary Prostate Cancer

Objectives: Emerging evidence supports a role for endothelin-1 (ET-1), endothelin A and B receptors (ET_A and ET_B, respectively), and neutral endopeptidase (NEP) in the progression of prostate carcinoma. In clinical trials for advanced prostate cancer, ET axis blockade significantly delayed the time to disease progression in a subset of patients. We examined ET axis expression in prostate cancer, prostatic intraepithelial neoplasia, and normal adjacent tissue and then analyzed the relationship of the protein levels with disease progression. Methods: The expression levels of ET_A, ET_B, and NEP were determined in 120 prostate cancer specimens obtained at surgery or biopsy by immunohistochemistry. In situ hybridization on a subset of the specimens was used to confirm the immunohistochemistry findings. Results: In regions of adenocarcinoma, immunohistochemistry analysis demonstrated high ET_A expression in 72% of the specimens. ET_A expression was significantly elevated with increased pathologic stage and grade. ET_B and NEP levels were significantly decreased in adenocarcinoma compared with normal adjacent tissue and prostatic intraepithelial neoplasia; however, reduced expression did not correlate with tumor grade or stage. Patients with prostate-specific antigen recurrence had significantly greater ET_A levels in their primary tumors than did patients who were disease free 5 years after prostatectomy. Patients with high ET_A expression in the adenocarcinoma regions with low ET_B and NEP had a significantly decreased interval to prostate-specific antigen progression compared with patients with low ET_A or high ET_B/NEP expression. Conclusions: These data suggest two patterns of ET_A expression in primary prostate cancer, with increased expression correlating with more advanced disease. The use of these expression patterns to identify patients more likely to respond to ET axis blockade might enhance treatment outcomes.