Breast cancer (BC) is among the most relevant cancer types worldwide. The late diagnosis and the subsequent delay in seeking treatment of BC represents a major issue among female population and attributes to poor prognosis and high mortality. Therefore, the search for new biomarkers with diagnostic, prognostic, and therapeutic purposes is still needed to assist in the clinical management of BC patients. Epigenetic alterations in cancer cells, which is accompanied by a plethora of deregulated enzymes like histone acetyltransferase and histone deacetylases, are increasingly recognized to play a critical role in carcinogenesis and in the response of cells to cellular stress induced by cancer therapeutics. The involvement of the histone acetyltransferases CREB-binding protein (CBP) and the General control non-depressible 5 (GCN5) in tumor formation and in regulating cellular response to stress have been previously reported. However, their implications in the cellular response of BC cells to genotoxic stress and in breast tumorigenesis remains poorly understood. Hence, this study aimed to investigate the molecular function of CBP under DNA damage in BC and in breast normal cells as well as to investigate the clinical significance of CBP and GCN5 as molecular markers and/or targets in BC. Cancer (MCF7 and T47D) and normal (HME1) breast cell lines were used to examine the expression, stability, and activity of CBP and its interaction with other proteins after DNA damage induction. In addition, immunofluorescence, western blot, comet assay, colony formation assay and mass spectrometry analysis were performed after CBP inhibition or downregulation under DNA damage. In order to assess the status of CBP and GCN5 in BC, their expression levels were analyzed in cell lines (by western blot), in patients' tissues (n=405) (by immunohistochemistry) and in the publicly available data iv from BC patients (n=1863). Our results showed that the protein level of CBP is stabilized in response to DNA double strand breaks (DSBs). T