Cholesterol metabolism has been implicated in prostate cancer pathogenesis. Here, we assessed the association of intratumoral mRNA expression of cholesterol synthesis enzymes, transporters, and regulators in tumor specimen at diagnosis and lethal prostate cancer, defined as mortality or metastases from prostate cancer in contrast to non-lethal disease without evidence of metastases after at least eight years of follow-up. We analyzed the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (n = 249) and the Physicians' Health Study (n = 153) as well as expectantly managed patients in the Swedish Watchful Waiting Study (n = 338). The expression of squalene monooxygenase (SQLE) was associated with lethal cancer in all three cohorts. Men with high SQLE expression (>1 standard deviation above the mean) were 8.3 times (95% confidence interval, 3.5 to 19.7) more likely to have lethal cancer despite therapy compared to men with the mean level of SQLE expression. Absolute SQLE expression was associated with lethal cancer independently from Gleason grade and stage, as was a SQLE expression ratio in tumor versus surrounding benign prostate tissue. Higher SQLE expression was tightly associated with increased histologic markers of angiogenesis. Collectively, this study establishes the prognostic value of intratumoral cholesterol synthesis as measured via SQLE, its second rate-limiting enzyme. SQLE expression at cancer diagnosis is prognostic for lethal prostate cancer both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease.
Cancer research. 2016 Jun 20 [Epub ahead of print]
Konrad H Stopsack, Travis A Gerke, Jennifer A Sinnott, Kathryn L Penney, Svitlana Tyekucheva, Howard D Sesso, Swen-Olof Andersson, Ove Andrén, James R Cerhan, Edward L Giovannucci, Lorelei A Mucci, Jennifer R Rider
Internal Medicine, Mayo Clinic ., Epidemiology, Harvard School of Public Health., Statistics, Ohio State University., Channing Division of Network Medicine, Department of Epidemiology, Brigham and Women's Hospital/Harvard Medical School, Harvard T.H. Chan School of Public Health., Biostatistics and Computational Biology, Dana-Farber Cancer Institute., Division of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School., Urology, Örebro University Hospital., Urology, Örebro University Hospital., Health Sciences Research, Mayo Clinic., Epidemiology, Harvard T.H. Chan School of Public Health., Epidemiology, Harvard T.H. Chan School of Public Health., Epidemiology, Boston University School of Public Health.