Importantly, combined PIN1- and CDK4/6-inhibition reactivates APC/C<sup>CDH1</sup> resulting in PIN1 degradation and an insurmountable G1 arrest that translates into synergistic anti-tumor activity against triple-negative breast cancer <i>in vivo.</i> Reciprocal inhibition of PIN1 and APC/C<sup>CDH1</sup> is a novel mechanism to control timely G1/S transition that can be harnessed for synergistic anti-cancer therapy. This evidence concerns the gene APC and triple-negative breast carcinoma.