p300 activity and subcellular localization associate with tumor aggressiveness and clinical outcome in triple-negative breast cancer

Hormone-independent breast cancers are aggressive malignancies with limited targeted therapeutic options. Epigenetic regulators such as the transcriptional cofactor p300 (EP300), which possesses histone acetyltransferase (HAT) activity, have been implicated in tumor progression; however, the contribution of p300 functional activity and subcellular localization to tumor aggressiveness and clinical outcome remains incompletely understood. Here, using triple-negative breast cancer (TNBC) as a model of hormone-independent aggressive tumors, we investigated the role of p300 activity and intracellular distribution through genetic silencing and pharmacological inhibition approaches. p300 depletion or HAT inhibition reduced tumor cell viability, induced apoptosis, and impaired metastatic dissemination both in vitro and in vivo. These effects were associated with alterations in epithelial–mesenchymal transition–related markers and cytoskeletal organization. Analysis of human TNBC specimens revealed a predominant cytoplasmic localization of p300 in tumor cells. Notably, exclusive cytoplasmic localization was associated with lower tumor stage and improved overall survival, independently of mutations affecting the HAT domain. Together, these findings identify p300 functional activity as a regulator of tumor aggressiveness and demonstrate that its subcellular localization provides clinically relevant prognostic information. Our results underscore the importance of considering both the activity and intracellular distribution of epigenetic regulators when evaluating their role as biomarkers and therapeutic targets in aggressive cancers.