Loss of BRCA1 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo.

BACKGROUND

Previous reports suggested a central role of BRCA1 in DNA-damage repair mechanisms elicited by cell exposure to anti-tumor agents. Here we studied if BRCA1-defective HCC1937 or BRCA1-reconstituted HCC1937/(WT)BRCA1 human breast cancer xenografts (HBCXs) generated in SCID mice were differentially sensitive to cisplatin (CDDP) in vivo and we investigated potential molecular correlates of this effect.

RESULTS

CDDP induced almost complete growth inhibition of BRCA1-defective HBCXs, while BRCA1-reconstituted HBCXs were only partially inhibited. Cell cycle analysis showed a significant S- and G(2)/M blockade in BRCA1-defective as compared with parental BRCA1-reconstituted cells. Comparative gene expression profiling of HCC1937 and HCC1937/(WT)BRCA1 showed upregulation of RAD52 and XRCC4, whereas ERCC1 and RRM1 were downregulated. Pathway finder analysis of gene arrays data indicated perturbations of major proliferation and survival pathways suggesting that BRCA1 is mostly involved in G(2)/M but also in G(1)/S-phase checkpoints as well as in several important signaling pathways, including IGF, VEGF, estrogen receptor, PI3K/AKT and EGF.

METHODS

HCC1937 or HCC1937/(WT)BRCA1 HBCXs were generated in SCID mice. Animals were then weekly treated with 5 mg/kg CDDP i.p. or with vehicle for 4 w. Tumor volume and mice survival were evaluated. Tumors were retrieved from animals 12 hours after the last treatment with CDDP or vehicle treatment and the cell suspension underwent cell cycle analysis. Differential gene expression and pathway modulation between HCC1937 and HCC1937/(WT)BRCA1 cells were also studied.

CONCLUSION

Our data suggest that BRCA1-defective in vivo HBCXs express a molecular scenario predictive of high sensitivity to platinum-derived compounds strongly supporting the rationale for prospective tailored clinical trials in hereditary breast cancer.