p300 involvement in the metastatic process of triple negative breast cancer

Abstract

Triple negative breast cancer (TNBC) are a heterogeneous group of tumors which lack specific molecular targets. Therefore, it is necessary to investigate potential tumor markers for this subtype of BC. Recent studies indicate that p300 has a pro-metastatic role in BC and we have previously shown that inhibition of p300 decreases cellular migration and invasion in a TNBC cell line. Therefore, in this work we aimed to analyze the expression and localization of p300 and its association with markers of tumor progression and clinic-pathological parameters in human TNBC. Also, we investigated the molecular mechanisms through which p300 inhibition impaired the processes previously mentioned. In TNBC biopsies (n= 45), we found that higher levels of cytoplasmic p300 correlates with lower tumor stages and a better overall patient survival (IHC, p<0.05). In TNBC (MDA-MB-231) and hormone-independent BC (LM3) cell lines, the genetic silencing of p300 induced an increase in the levels of membrane E-cadherin, a decrease of nuclear ß-catenin and in the number of stress fibers compared with the control (IF, p<0.05). In a mouse xenograft model of MDA-MB-231 we found an increase in E-cadherin and a decrease in nuclear ß-catenin expression (IHC, p<0.05) in the tumors of animals injected with VV59, a specific pharmacological inhibitor of p300. Also, in such group of mice, we found a significant reduction in the number of lung metastases respect to control group (p<0.05). Altogether these results demonstrate an antitumor role for p300 inhibition or cytoplasmic translocation in TNBC.