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

Abstract

Background: Previous reports suggested a central role of BRCA1 in DNA-damage repair mechanisms elicited by cell exposure to antitumour agents. Here we studied if BRCA1-defective HCC1937 or BRCA1-reconstituted HCC1937/ WTBRCA1 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 G2/M blockade in BRCA1-defective as compared with parental BRCA1-reconstituted cells. Comparative gene expression profiling of HCC1937 and HCC1937/WTBRCA1 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 G2/M but also in G 1/S-phase checkpoints as well as in several important signaling pathways, including IGF, VEGF, oestrogen receptor, PI3K/AKT and EGF. Methods: HCC1937 or HCC1937/WTBRCA1 HBCXs were generated in SCID mice. Animals were then weekly treated with 5 mg/kg CDDP i.p. or with vehicle for 4 weeks. Tumour volume and mice survival were evaluated. Tumours 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/WTBRCA1 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. ©2009 Landes Bioscience.