CDKN1A/p21 Influences the Survival and Expansion of Breast Cancer Stem Cells after Oxidative Damage

Breast cancer remains one of the most prevalent malignancies among women worldwide, and despite advances in therapy and treatment options, tumour relapse and metastasis remain major clinical challenges, largely driven by the breast cancer stem cells (BCSCs) niche that resists conventional treatments and regenerates tumours. In breast cancer, where approximately 30% of patients who initially respond to treatment ultimately relapse and die of metastatic disease, targeting BCSCs is critical for improving patient outcomes. Cyclin-dependent kinase inhibitor 1A/p21 (CDKN1A/p21) is a multifunctional protein that is known primarily for its role in regulating the cell cycle in response to DNA damage. However, in this study, we aimed to explore the role of CDKN1A/p21 in the survival and expansion of BCSCs.

We used three-dimensional in vitro models to assess the influence of CDKN1A/p21 expression on the survival of BCSCs both under basal conditions and after oxidative damage. Spatial transcriptomics analysis and chromatin immunoprecipitation-quantitative PCR (qPCR) were used to investigate the role of CDKN1A/p21 in the regulation and control of BCSC gene expression signatures.

We demonstrated that alterations in CDKN1A/p21 expression affect the ability of breast cancer cells to grow and survive after oxidative damage. 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.

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.