Activation of TP53 target genes in the primary response of triple-negative breast cancer cells to doxorubicin treatment

Abstract

Among the DNA-damaging agents commonly used in clinical settings doxorubicin has emerged as one of the most effective treatments for Triple-negative breast cancer (TNBC). Our limited understanding about the molecular mechanisms underlying the short- and long-term responses of TNBC cells to DNA damage induced by drugs like doxorubicin is a hurdle to improve the efficacy of the treatment or overcome the drug resistance. In this study, we aimed to elucidate the immediate response of the TNBC cells to doxorubicin and compare these responses with those of doxorubicin-resistant cells through transcriptome analysis. Transcriptome analysis revealed that doxorubicin significantly upregulates the expression of TP53 target genes, including CDKN1A, TIGAR, TP53INP1, PPM1D, and ACER2. Notably, doxorubicin-resistant TNBC cells failed to increase the expression of these genes, except for CDKN1A, upon doxorubicin treatment. Moreover, treatment with etoposide as another DNA-damaging drug increased the expression of CDKN1A, TP53INP1, and ACER2 in a TP53-independent manner. Collectively, this study highlights the critical role of TP53 target genes in the immediate response of TNBC cells to DNA-damaging agents like doxorubicin and etoposide. It also reveals distinct molecular mechanisms regulating their expression in resistant versus sensitive cells, offering potential therapeutic targets to improve treatment strategies for TNBC. © The Author(s) 2025.