BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma

Busacca, Sara, Sheaff, Michael, Arthur, Kenneth, Gray, Steven G, O'Byrne, Kenneth J., Richard, Derek J., Soltermann, Alex, Opitz, Isabelle, Pass, Harvey, Harkin, D Paul, Quinn, Jennifer E, & Fennell, Dean A (2012) BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma. The Journal of Pathology, 227(2), pp. 200-208.

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Abstract

The rapeutic options for malignant pleural mesothelioma (MPM) are limited despite the increasing incidence globally. The vinca alkaloid vinorelbine exhibits clinical activity; however, to date, treatment optimization has not been achieved using biomarkers. BRCA1 regulates sensitivity to microtubule poisons; however, its role in regulating vinorelbine-induced apoptosis in mesothelioma is unknown. Here we demonstrate that BRCA1 plays an essential role in mediating vinorelbine-induced apoptosis, as evidenced by (1) the strong correlation between vinorelbine sensitivity and BRCA1 expression level; (2) induction of resistance to vinorelbine by BRCA1 using siRNA oligonucleotides; (3) dramatic down-regulation of BRCA1 following selection for vinorelbine resistance; and (4) the re-activation of vinorelbine-induced apoptosis following re-expression of BRCA1 in resistant cells. To determine whether loss of BRCA1 expression in mesothelioma was potentially relevant in vivo, BRCA1 immunohistochemistry was subsequently performed on 144 primary mesothelioma specimens. Loss of BRCA1 protein expression was identified in 38.9% of samples. Together, these data suggest that BRCA1 plays a critical role in mediating apoptosis by vinorelbine in mesothelioma, warranting its clinical evaluation as a predictive biomarker. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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ID Code: 55930
Item Type: Journal Article
Refereed: Yes
Keywords: malignant pleural mesothelioma, vinorelbine, BRCA1, treatment resistance
DOI: 10.1002/path.3979
ISSN: 1096-9896
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Cell Biology (111201)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Therapy (excl. Chemotherapy and Radiation Therapy) (111204)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2012 John Wiley & Sons
Deposited On: 20 Dec 2012 05:45
Last Modified: 12 Dec 2013 01:27

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