|Abstract: ||Resistance to chemotherapeutic agents is the main obstacle to the effective breast cancer management. Therefore, it is important to elucidate the molecular mechanisms of chemoresistance and develop novel therapeutic strategies in order to overcome drug resistance. In this work, I found that FOXM1 is a critical mediator of epirubicin and paclitaxel resistance in MCF-7 breast cancer cell lines. FOXM1 expression was upregulated in both epirubicin resistant MCF-7 (MCF-7 EpiR) and paclitaxel resistant MCF-7 (MCF-7 TaxR) cells compared to sensitive MCF-7 cells. Interestingly, its depletion dramatically impaired the clonogenic survival and significantly induced cellular senescence in the resistant cells. In addition, I identified two novel downstream FOXM1 targets, NBS1 and KIF20A, involved in epirubicin and paclitaxel resistance, respectively.
Firstly, I found that FOXM1 transcriptionally regulated NBS1 expression to modulate HR-mediated DSB repair and epirubicin resistance. Overexpression of FOXM1 and NBS1 lead to the enhancement of HR efficiency to eliminate epirubicin-induced DNA damage. Conversely, similar to FOXM1, depletion of NBS1 also sensitised both MCF-7 and MCF-7 EpiR cells to epirubicin by inducing cellular senescence. Secondly, I identified the mitotic kinesin KIF20A as a direct downstream target of FOXM1, participating in the mitotic spindle formation and paclitaxel resistance. Depletion of KIF20A caused mitotic spindle abnormalities, inhibition of cell growth as well as the induction of senescent cells in both MCF-7 and MCF-7 TaxR cells. Consistently, immunohistochemical analysis of breast cancer patient samples revealed that high expression levels of FOXM1, NBS1 and KIF20A are strongly correlated with poor prognosis in breast cancer, supporting a physiological role of FOXM1 and its novel targets in genotoxic drug resistance.
Collectively, these findings suggests that FOXM1 and its targets, NBS1 and KIF20A, could be reliable prognostic markers for monitoring treatment efficiency as well as promising targets for therapeutic intervention to overcome epirubicin and paclitaxel resistance in breast cancer.|