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BRCA1 is an essential mediator of vinorelbine induced apoptosis in mesothelioma


Busacca, S; Sheaff, M; Arthur, K; Gray, S G; O'Byrne, K J; Richard, D J; Soltermann, A; Opitz, I; Pass, H; Harkin, D P; Quinn, J E; Fennell, D A (2011). BRCA1 is an essential mediator of vinorelbine induced apoptosis in mesothelioma. Journal of Pathology:1-28.

Abstract

Therapeutic 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 downregulation 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, this data suggests BRCA1 plays a critical role in mediating apoptosis by vinorelbine in mesothelioma, warranting its clinical evaluation as a predictive biomarker. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Therapeutic 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 downregulation 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, this data suggests BRCA1 plays a critical role in mediating apoptosis by vinorelbine in mesothelioma, warranting its clinical evaluation as a predictive biomarker. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Surgical Pathology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Thoracic Surgery
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2011
Deposited On:26 Feb 2012 17:46
Last Modified:05 Apr 2016 15:38
Publisher:Wiley-Blackwell
ISSN:0022-3417
Publisher DOI:https://doi.org/10.1002/path.3979
PubMed ID:22190288
Permanent URL: https://doi.org/10.5167/uzh-59453

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