Distinct Patterns of Endothelin Axis Expression in Primary Prostate Cancer

Abstract

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. 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. 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. 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.