Mechanistically, we found that CDKN1A/p21 directly binds to the promoter and regulates the expression of CD44, SPP1, and TMSB10, a combination gene signature that is associated with a greater probability of recurrence and metastasis in breast cancer patients.<h4>Conclusions</h4>We propose that changes in gene regulation mediated by CDKN1A/p21 possibly contribute to cancer stem cell survival after oxidative damage, thus making CDKN1A/p21 a promising target for future drug discovery projects aimed at addressing the issue of therapeutic resistance and breast cancer metastasis. Here, CD44 is linked to breast cancer.