title: BRCA1 loss induces GADD153-mediated doxorubicin resistance in prostate cancer.
abstract: BRCA1 plays numerous roles in the regulation of genome integrity and chemoresistance. Although BRCA1 interaction with key proteins involved in DNA repair is well known, its role as a coregulator in the transcriptional response to DNA damage remains poorly understood. In this study, we show that BRCA1 plays a central role in the transcriptional response to genotoxic stress in prostate cancer. BRCA1 expression mediates apoptosis, cell-cycle arrest, and decreased viability in response to doxorubicin treatment. Xenograft studies using human prostate carcinoma PC3 cells show that BRCA1 depletion results in increased tumor growth. A focused survey of BRCA1-regulated genes in prostate carcinoma reveals that multiple regulators of genome stability and cell-cycle control, including BLM, FEN1, DDB2, H3F3B, BRCA2, CCNB2, MAD2L1, and GADD153, are direct transcriptional targets of BRCA1. Furthermore, we show that BRCA1 targets GADD153 promoter to increase its transcription in response to DNA damage. Finally, GADD153 depletion significantly abrogates BRCA1 influence on cell-cycle progression and cell death in response to doxorubicin treatment. These findings define a novel transcriptional pathway through which BRCA1 orchestrates cell fate decisions in response to genotoxic insults, and suggest that BRCA1 status should be considered for new chemotherapeutic treatment strategies in prostate cancer.
authors.affiliation: Laboratory of Cancer and Apoptosis, Department of Biological Chemistry, School of Scences, University of Buenos Aires, CONICET, Buenos Aires, Argentina.
authors.forename: Paola
authors.initials: P
authors.lastname: De Luca
authors.forename: Elba S
authors.initials: ES
authors.lastname: Vazquez
authors.forename: Cristian P
authors.initials: CP
authors.lastname: Moiola
authors.forename: Florencia
authors.initials: F
authors.lastname: Zalazar
authors.forename: Javier
authors.initials: J
authors.lastname: Cotignola
authors.forename: Geraldine
authors.initials: G
authors.lastname: Gueron
authors.forename: Kevin
authors.initials: K
authors.lastname: Gardner
authors.forename: Adriana
authors.initials: A
authors.lastname: De Siervi
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D019313:BRCA1 Protein; D051742:Transcription Factor CHOP; D004317:Doxorubicin