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

Sara Busacca, Michael Sheaff, Kenneth Arthur, Steven G Gray, Kenneth J O'Byrne, Derek J Richard, Alex Soltermann, Isabelle Opitz, Harvey Pass, D Paul Harkin, Jennifer Quinn-O'Brien, Dean A Fennell

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15 Citations (Scopus)

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 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.
Original languageEnglish
Pages (from-to)200-208
Number of pages9
JournalJournal of Pathology
Volume227
Issue number2
DOIs
Publication statusPublished - Jun 2012

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    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-O'Brien, J., & Fennell, D. A. (2012). BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma. Journal of Pathology, 227(2), 200-208. https://doi.org/10.1002/path.3979