Figure 6.

HER2 inhibition in a CDC25A overexpression context restores the DDR through a PI3K/AKT-dependent mechanism. In CDC25A-positive breast cancer cells, high levels of CDC25A, pushing the cell throughout the cell cycle transition, may induce an impaired DDR machinery, bypassing the DNA damage-induced cell cycle arrest. In HER2/CDC25A double-positive breast cancer cells, such DDR evasion could be enhanced by HER2 through CDC25A stabilization (A). In this context, HER2 down-regulation leads to AKT inhibition that stops its inhibitory action on CHK1/CHK2; the activation of the checkpoint kinases promotes CDC25A degradation and restores the DDR in checkpoint-proficient cells (B).