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Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair
Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, S-17165 Stockholm, Sweden.;Cent Hosp Vasteras, Dept Urol, S-72189 Vasteras, Sweden..
Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, S-17165 Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Cent Hosp Vasteras, Dept Pathol, S-72189 Vasteras, Sweden..
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2015 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, no 312, 312re11Article in journal (Refereed) Published
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Abstract [en]

Chemical castration improves responses to radiotherapy in prostate cancer, but the mechanism is unknown. We hypothesized that this radiosensitization is caused by castration-mediated down-regulation of non-homologous end joining (NHEJ) repair of DNA double-strand breaks (DSBs). To test this, we enrolled 48 patients with localized prostate cancer in two arms of the study: either radiotherapy first or radiotherapy after neoadjuvant castration treatment. We biopsied patients at diagnosis and before and after castration and radiotherapy treatments to monitor androgen receptor, NHEJ, and DSB repair in verified cancer tissue. We show that patients receiving neoadjuvant castration treatment before radiotherapy had reduced amounts of the NHEJ protein Ku70, impaired radiotherapy-induced NHEJ activity, and higher amounts of unrepaired DSBs, measured by gamma-H2AX foci in cancer tissues. This study demonstrates that chemical castration impairs NHEJ activity in prostate cancer tissue, explaining the improved response of patients with prostate cancer to radiotherapy after chemical castration.

Place, publisher, year, edition, pages
2015. Vol. 7, no 312, 312re11
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Cancer and Oncology
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URN: urn:nbn:se:uu:diva-269976DOI: 10.1126/scitranslmed.aac5671ISI: 000365237300002OAI: oai:DiVA.org:uu-269976DiVA: diva2:885599
Funder
Swedish Research CouncilEU, European Research CouncilAFA InsuranceSwedish Cancer SocietyTorsten Söderbergs stiftelseAstraZeneca
Available from: 2015-12-19 Created: 2015-12-19 Last updated: 2017-12-01Bibliographically approved

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Tanoglidi, Anna

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