There is evidence that p300, a transcriptional co-factor and a
lysine acetyl-
transferase, could play a role both as an
oncoprotein and as a
tumor suppressor, although little is known regarding its role in
breast cancer (BC). First we investigated the role p300 has on BC by performing pharmacological inhibition of p300 acetyl-
transferase function and analyzing the effects on cell count, migration and invasion in LM3 murine
breast cancer cell line and on
tumor progression in a syngeneic murine model. We subsequently studied p300
protein expression in human BC biopsies and evaluated its correlation with clinical and histopathological parameters of the patients. We observed that inhibition of p300 induced apoptosis and reduced migration and invasion in cultured LM3 cells. Furthermore, a significant reduction in
tumor burden, number of lung
metastases and number of
tumors invading the abdominal cavity was observed in a syngeneic
tumor model of LM3 following treatment with the p300 inhibitor. This reduction in
tumor burden was accompanied by a decrease in the mitotic index and Ki-67 levels and an increase in Bax expression. Moreover, the analysis of p300 expression in human BC samples showed that p300 immunoreactivity is significantly higher in the cancerous tissues than in the non-malignant mammary tissues and in the histologically normal adjacent tissues. Interestingly, p300 was observed in the cytoplasm, and the rate of cytoplasmic p300 was higher in BC than in non-
tumor tissues. Importantly, we found that cytoplasmic localization of p300 is associated with a longer overall survival time of the patients. In conclusion, we demonstrated that inhibition of the
acetylase function of p300 reduces both cell count and invasion in LM3 cells, and decreases
tumor progression in the animal model. In addition, we show that the presence of p300 in the cytoplasm correlates with increased survival of patients suggesting that its nuclear localization is necessary for the pro-tumoral effects.