Increased cholesterol synthesis via squalene monooxygenase to predict lethal prostate cancer.

Abstract

77 Background: Prostate cancer cells rely on cholesterol for proliferation and androgen production. We recently demonstrated that increased expression of the second key enzyme of cholesterol synthesis, squalene monooxygenase (SQLE), is associated with higher prostate cancer-specific mortality (PCSM). We here validate findings in two additional prospective studies and investigate putative mechanisms. Methods: We analyzed the prospective prostatectomy cohorts within the Health Professionals Follow-up Study (HPFS) and the Physicians’ Health Study (PHS) as well as initially expectantly managed patients in the Swedish Watchful Waiting Study (SWWS). 258 lethal cancer cases and 469 patients who survived > 8 years without metastases were included. SQLE mRNA was measured in tumor specimens at diagnosis of all patients and in benign prostate tissue of 197 patients. Markers of tumor angiogenesis were assessed via immunohistochemistry in 169 HPFS patients. We estimated multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. Results: Higher SQLE expression was confirmed to be predictive of higher PCSM in the validation prostatectomy cohort PHS. Combining the two prostatectomy cohorts, men with high SQLE expression ( > 1 standard deviation above the mean) were 6.7 times (95% CI, 2.9 to 15.8; p < 0.001) more likely to die from their cancer compared to men with the mean level of SQLE expression. A 10% higher ratio of SQLE mRNA expression in tumor vs. benign prostate tissue of the same patient was predictive of 42% higher PCSM (95% CI, 15% to 74%). Higher SQLE expression was strongly associated with increased angiogenesis markers (all p ≤ 0.001). This increased risk associated with high SQLE expression was not modified by statin use (p ≥ 0.52). In initially untreated patients in SWWS, a more modest association of tumor SQLE expression with PCSM was observed (p = 0.047). Conclusions: SQLE, the second rate-limiting enzyme of cholesterol synthesis, is associated with prostate cancer progression. Its expression at cancer diagnosis is predictive of lethal disease both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease.