title: BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma.
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.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Busacca
authors.forename: Michael
authors.initials: M
authors.lastname: Sheaff
authors.forename: Kenneth
authors.initials: K
authors.lastname: Arthur
authors.forename: Steven G
authors.initials: SG
authors.lastname: Gray
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Byrne
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Richard
authors.forename: Alex
authors.initials: A
authors.lastname: Soltermann
authors.forename: Isabelle
authors.initials: I
authors.lastname: Opitz
authors.forename: Harvey
authors.initials: H
authors.lastname: Pass
authors.forename: D Paul
authors.initials: DP
authors.lastname: Harkin
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Quinn
authors.forename: Dean A
authors.initials: DA
authors.lastname: Fennell
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010997:Pleural Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D014162:Transfection; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; D014747:Vinblastine; D000077235:Vinorelbine