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Cholesterol uptake and regulation in high-grade and lethal prostate cancers
Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States.
Department of Internal Medicine, Mayo Clinic, Rochester MN, United States.
Department of Urology, School of Health and Medical Sciences, University of Örebro, Örebro, Sweden.
Department of Urology, School of Health and Medical Sciences, University of Örebro, Örebro, Sweden.
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2017 (English)In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 38, no 8, 806-811 p.Article in journal (Refereed) Published
Abstract [en]

Lethal prostate cancers have higher expression of squalene monooxygenase (SQLE), the second rate-limiting enzyme of cholesterol synthesis. Preclinical studies suggested that aberrant cholesterol regulators, receptors and transporters contribute to cholesterol accumulation uniformly. We assessed their association with features of aggressive cancers. In the prospective prostate cancer cohorts within the Health Professional Follow-up Study, the Physicians' Health Study and the Swedish Watchful Waiting Study, tumor mRNA expression profiling was performed. Lethal disease was defined as mortality or metastases from prostate cancer (n = 266) in contrast to non-lethal disease without metastases after >8 years of follow-up (n = 476). Associations with Gleason grade were additionally assessed using The Cancer Genome Atlas primary prostate cancer dataset (n = 333). Higher Gleason grade was associated with lower LDLR expression, lower SOAT1 and higher SQLE expression. Besides high SQLE expression, cancers that became lethal despite primary treatment were characterized by low LDLR expression (odds ratio for highest versus lowest quintile, 0.37; 95% CI 0.18-0.76) and by low SOAT1 expression (odds ratio, 0.41; 95% CI 0.21-0.83). The association of LDLR expression and lethality was not present in tumors with high IDOL expression. ABCA1, PCSK9 or SCARB1 expressions were not associated with Gleason grade or lethal cancer. In summary, prostate cancers that progress to lethal disease rely on de novo cholesterol synthesis (via SQLE), rather than transcellular uptake (via LDLR) or cholesterol esterification (via SOAT1). These results may help design pharmacotherapy for high-risk patients.

Place, publisher, year, edition, pages
Oxford University Press, 2017. Vol. 38, no 8, 806-811 p.
National Category
Medical Genetics Cancer and Oncology
Identifiers
URN: urn:nbn:se:oru:diva-61799DOI: 10.1093/carcin/bgx058ISI: 000406831800006PubMedID: 28595267Scopus ID: 2-s2.0-850284139262-s2.0-85028413926OAI: oai:DiVA.org:oru-61799DiVA: diva2:1151359
Note

Funding agencies:

National Institutes of Health UM1 CA167552 

Dana-Farber/Harvard Cancer Center Specialized Programs of Research Excellence program in Prostate Cancer 5P50CA090381-08 

National Cancer Institute CA141298 CA133891  CA097193  CA34944  CA40360  HL26490  HL34595 

Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2018-01-13Bibliographically approved

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Andrén, OveAndersson, Swen-Olof

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