Overall, our results indicate that the chemotherapy-driven increases in the CDKN1A/PTN/PTPRZ1 axis are critical intrinsic factors of therapy-induced chemoresistance in breast cancer and that disrupting the CDKN1A/PTN/PTPRZ1 axis is a novel strategy to enhance the chemosensitivity of breast cancer, especially in the triple-negative subtype. This evidence concerns the gene CDKN1A and breast carcinoma.