BRCA1 and GADD45 mediated G2/M cell cycle arrest in response to antimicrotubule agents

BRCA1 is a tumour suppressor gene implicated in the predisposition to early onset breast and ovarian cancer. We have generated cell lines with inducib le expression of BRCA1 to evaluate its role in mediating the cellular respo nse to various chemotherapeutic drugs commonly used in the treatment of bre ast and ovarian cancer. Induction of BRCA1 in the presence of Taxol and Vin cristine resulted in a dramatic increase in cell death; an effect that was preceded by an acute arrest at the G2/M phase of the cell cycle and which c orrelated with BRCA1 mediated induction of GADD45. A proportion of the arre sted cells were blocked in mitosis suggesting activation of both a G2 and a mitotic spindle checkpoint. In contrast, no specific interaction was obser ved between BRCA1 induction and treatment of cells with a range of DNA dama ging agents including Cisplatin and Adriamycin. Inducible expression of GAD D45 in the presence of Taxol induced both G2 and mitotic arrest in these ce lls consistent with a role for GADD45 in contributing to these effects. Our results support a role for both BRCA1 and GADD45 in selectively regulating a G2/M checkpoint in response to antimicrotubule agents and raise the poss ibility that their expression levels in cells may contribute to the toxicit y observed with these compounds.