BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis.
We have evaluated the role played by BRCA1 in mediating the phenotypic response to a range of chemotherapeutic agents commonly used in cancer treatment. Here we provide evidence that BRCA1 functions as a differential mediator of chemotherapy-induced apoptosis. Specifically, we demonstrate that BRCA1 mediates sensitivity to apoptosis induced by antimicrotubule agents but conversely induces resistance to DNA-damaging agents. These data are supported by a variety of experimental models including cells with inducible expression of BRCA1, siRNA-mediated inactivation of endogenous BRCA1, and reconstitution of BRCA1-deficient cells with wild-type BRCA1. Most notably we demonstrate that BRCA1 induces a 10-1000-fold increase in resistance to a range of DNA-damaging agents, in particular those that give rise to double-strand breaks such as etoposide or bleomycin. In contrast, BRCA1 induces a >1000-fold increase in sensitivity to the spindle poisons, paclitaxel and vinorelbine. Fluorescence-activated cell sorter analysis demonstrated that BRCA1 mediates G(2)/M arrest in response to both antimicrotubule and DNA-damaging agents. However, poly(ADP-ribose) polymerase and caspase-3 cleavage assays indicate that the differential effect mediated by BRCA1 in response to these agents occurs through the inhibition or induction of apoptosis. Therefore, our data suggest that BRCA1 acts as a differential modulator of apoptosis depending on the nature of the cellular insult.
Quinn
Jennifer E
JE
Department of Oncology, Cancer Research Centre, Queen's University Belfast, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, Northern Ireland, U.K.
Kennedy
Richard D
RD
Mullan
Paul B
PB
Gilmore
Paula M
PM
Carty
Michael
M
Johnston
Patrick G
PG
Harkin
D Paul
DP
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D019313:BRCA1 Protein / Q000096:biosynthesis / Q000502:physiology*; D001761:Bleomycin / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000502:physiology; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology*; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine
D000972:Antineoplastic Agents, Phytogenic; D019313:BRCA1 Protein; D001761:Bleomycin; D014747:Vinblastine; D005047:Etoposide; D017239:Paclitaxel; D002945:Cisplatin; D000077235:Vinorelbine