Pharmacological Inhibition Of P300 Displays Antimetastatic Activity In Triple Negative Breast Cancer

Abstract

Triple negative breast cancer (TNBC) is a molecular subtype of BC that is known for having a poor prognosis and limited therapeutic options. Therefore, it is necessary to investigate potential therapeutic targets for this pathology. A relationship between p300 and cancer has been demonstrated; but its role remains unclear, as it has been documented both as a tumor suppressor and an oncoprotein. Previously, we have shown that pharmacological inhibition of p300 has an antitumoral effect in the hormone-independent breast cancer cell line, LM3 and its syngeneic murine model. Further, we observed that pharmacological inhibition of p300 reduces migration, invasion and adhesion processes in TNBC MDA-MB-231 cells, indicating the need to further investigate the involved molecules. It is known that E-cadherin and β-catenin are key proteins in adhesion processes between epithelial cells and a decrease in their membrane expression is linked to a pro-tumor phenotype. Therefore, we proposed to investigate the effect of pharmacological inhibition of p300 on stress fiber formation and E- cadherin and β-catenin expression in TNBC cell line and its xenograft model. MDA-MB-231 cells were treated with VV59 (inhibitor of p300 histone acetyltransferase activity) or its vehicle. We detected an increase in E-cadherin and in membrane β-catenin expression in cells treated with VV59 compared to vehicle (immunofluorescence, p˂0.01). In addition, cells stained with fluorescently labeled phalloidin revealed a decrease in stress fibers in cells treated with VV59 compared to vehicle (p˂0.01). In a murine xenograft model of MDA-MB-231 we detected an increase in E-cadherin and in membrane β-catenin expression (immunohistochemistry, p<0.01) in the tumors of animals injected with VV59 compared to the control group. Also, in such a group of mice, we found a significant reduction in the number of lung metastases with respect to the control group (p<0.05). These results suggest a prometastatic role of p300 in TNBC.