DE SIERVI Adriana
BRCA1 loss induces GADD153-mediated doxorubicin resistance in prostate cancer.
DE LUCA P; VAZQUEZ E; MOIOLA C; ZALAZAR F; COTIGNOLA J; GUERON G; GARDNER K; DE SIERVI A
MOLECULAR CANCER RESEARCH
AMER ASSOC CANCER RESEARCH
Año: 2011 vol. 9 p. 1078 - 1090
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 co-regulator 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 demonstrate 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 demonstrate 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.