Christophe LACHAUD - FAN1 has a new playmate to promote Breast Cancer resistance to chemotherapy!

Breast cancer is the second leading cause of cancer-related death among women. Usually, chemotherapy treatment is performed in association with surgery, radiation or hormone therapy, providing an increased outcome to patients. However, tumors can develop resistance to different drugs, progressing for a more aggressive phenotype. Here we report a role for the nuclease FAN1 in limiting chromosome instability and in supporting breast tumor resistance to treatment with doxorubicin and paclitaxel. This function is mediated by both the UBZ and the nuclease domain. We show that the interaction of the UBZ domain of FAN1 with PCNA prevents DNA damage during replication stress induced by doxorubicin whereas the interaction of the UBZ domain of FAN1 with ANLN prevents mitotic stress. Moreover, we show that over expression of FAN1 is associated to breast cancer resistance to doxorubicin and paclitaxel. Accordingly, Knocking out FAN1 increases cell sensitivity to docetaxel and paclitaxel treatment, suggesting the need of developing FAN1 inhibitors to reverse breast tumor resistance to chemotherapy.