Intratumoral Sterol-27-Hydroxylase () Expression in Relation to Cholesterol Synthesis and Vitamin D Signaling and Its Association with Lethal Prostate Cancer.

BACKGROUND

Higher intratumoral cholesterol synthesis is associated with a worse prognosis in prostate cancer. The vitamin D-regulated enzyme sterol-27-hydroxylase (CYP27A1) converts cholesterol to 27-hydroxycholesterol, potentially lowering intracellular cholesterol levels. We hypothesized that low expression is associated with high cholesterol synthesis, low vitamin D signaling, and higher risk of lethal prostate cancer.

METHODS

In 404 patients from the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (HPFS) and the Physicians' Health Study (PHS), we assessed intratumoral expression and proxies of cholesterol synthesis using transcriptome profiling, prediagnostic plasma 25-hydroxyvitamin D [25(OH)D; = 132], and intratumoral vitamin D receptor protein expression (VDR; = 300). Patients were followed for metastases and prostate cancer mortality (lethal cancer; median follow-up, 15.3 years).

RESULTS

expression was lower in tumors with higher Gleason grade and higher expression of cholesterol synthesis enzymes, including the second rate-limiting enzyme, . We did not detect consistent associations between and 25(OH)D, VDR, or mRNA expression. Lower was associated with higher risk of lethal cancer in both cohorts, independent of [adjusted OR for lowest vs. highest quartile of , 2.64; 95% confidence interval (CI), 1.24-5.62]. This association was attenuated when additionally adjusting for Gleason grade (OR, 1.76; 95% CI, 0.75-4.17).

CONCLUSIONS

Low expression was associated with higher cholesterol synthesis and a higher risk of lethal disease.

IMPACT

These observations further support the hypothesis that intratumoral cholesterol accumulation through higher synthesis and decreased catabolism is a feature of lethal prostate cancer.