Abstract

Background

The Forkhead Box M1 (FOXM1) protein is frequently upregulated in cancer and can transcriptionally regulate a number of DNA damage repair genes, including Rad51. In normal mitotic cells Foxm1 expression is tightly controlled, however in cancer cells, Foxm1 overexpression is common, and it has therefore been identified as a promising therapeutic target. Previous studies have shown that reduced RAD51 levels sensitise cancer cells to the FDA-approved PARP inhibitor, Olaparib. Therefore, targeting FOXM1, in combination with Olaparib, may be a novel therapeutic strategy.

Method

To investigate this hypothesis, we analysed the expression of RAD51 and FOXM1 in a panel of breast cancer cell lines. We next used this panel to determine the effect of the FOXM1 inhibitor, Thiostrepton and Olaparib alone, and in combination, on cell viability and induction of DNA damage, using γH2AX foci detection.

Results

In our breast cancer cell line panel, we observed a correlation in FOXM1 and RAD51 expression levels. Inhibition of FOXM1 with Thiostrepton, results in a corresponding decrease in RAD51 expression. Upon treatment with Thiostrepton and Olaparib alone and in combination, we have identified a synergistic reduction in cell viability upon combined treatment.

Conclusion

Taken together, our work suggests, for the first time, that FOXM1 regulates Rad51 in breast cancer cells, and that inhibiting FOXM1 with Thiostrepton could sensitise breast cancer cells to Olaparib.