Calcium-Sensing Receptor Tumor Expression and Lethal Prostate Cancer Progression

Abstract

Context: Prostate cancer metastases preferentially target bone, and the calcium-sensing receptor (CaSR) may play a role in promoting this metastatic progression. Objective: We evaluated the association of prostate tumor CaSR expression with lethal prostate cancer. Design: Avalidated CaSR immunohistochemistry assay was performed on tumor tissue microarrays. Vitamin D receptor (VDR) expression and phosphatase and tensin homolog tumor status were previously assessed in a subset of cases by immunohistochemistry. Cox proportional hazards models adjusting for age and body mass index at diagnosis, Gleason grade, and pathological tumor node metastasis stage were used to estimate hazard ratios (HR) and95% confidence intervals (CI) for the association of CaSR expression with lethal prostate cancer. Setting: The investigation was conducted in the Health Professionals Follow-up Study and Physicians' Health Study. Participants: We studied 1241 incident prostate cancer cases diagnosed between 1983 and 2009. Main Outcome: Participants were followed up or cancer-specific mortality or development of metastatic disease. Results: On average, men were followed up 13.6 years, during which there were 83 lethal events. High CaSR expression was associated with lethal prostate cancer independent of clinical and pathological variables (HR 2.0; 95% CI 1.2-3.3). Additionally, there was evidence of effect modification by VDR expression; CaSR was associated with lethal progression among men with low tumor VDR expression (HR 3.2; 95% CI 1.4-7.3) but not in cases with high tumor VDR expression (HR 0.8; 95% CI 0.2-3.0). Conclusions: Tumor CaSR expression is associated with an increased risk of lethal prostate cancer, particularly in tumors with low VDR expression. These results support further investigating the mechanism linking CaSR with metastases.