cAMP regulated EPAC1 supports microvascular density, angiogenic and metastatic properties in a model of triple negative breast cancer

Abstract

Breast cancer is a leading cause of cancer-related mortality in women. Triple-negative breast cancer (TNBC; HER2-, ER-/PR-) is an aggressive subtype prone to drug resistance and metastasis, which is characterized by high intratumor microvascular density (iMVD) resulting from angiogenesis. However, the mechanisms contributing to the aggressive phenotypes of TNBC remain elusive. We recently reported that down-regulation of exchange factor directly activated by cyclic AMP (cAMP), also known as EPAC1, leads to a reduction in metastatic properties including proliferation and cell migration in TNBC cell lines. Here, we report that EPAC1 supports TNBC-induced angiogenesis, tumor cell migration and invasiveness as well as pro-metastatic phenotypes in endothelial cells induced through the tumor secretome. Using an approach that integrates proteomics with bioinformatics and gene ontologies, we elucidate that EPAC1 supports a tumor-secreted network of angiogenic, cell adhesion and cell migratory pathways. Using confocal microscopy, we show that signaling molecules involved in focal adhesion, including Paxillin and MENA, are down-regulated in the absence of EPAC1, and electric cell substrate impedance sensing technique confirmed a role for EPAC1 on TNBC-induced endothelial cell permeability. Finally, to provide a translational bridge, we studied iMVD and therapy response using a primary human tumor explant assay, CANscriptTM, which suggests a link between therapy-modulated neovascularization and drug sensitivity. These data provide mechanistic insight into the role of EPAC1 in regulating the tumor microenvironment, iMVD and cancer cell-induced angiogenesis, a dynamic mechanism under drug pressure that may associate to treatment failure.

Visualization and bibliometric analysis of cAMP signaling system research trends and hotspots in cancer

“…EPAC1 regulated the metastasis of melanoma cells through syndecan-2 translocation, heparin sulfate (HS) modification and activation of endoplasmic reticulum Ca 2+ release via the phospholipase C (PLC)/ inositol triphosphate (IP3) receptor pathway 49 , 50 , 51 . In triple-negative breast cancer (TNBC) cells, the down-regulation of EPAC1 could reduce the metastasis of TNBC cell lines 52 .…”

POPDC3 is a potential biomarker for prognosis and radioresistance in patients with head and neck squamous cell carcinoma

“…POPDC3 is a member of the popeye domain-containing family which consists of three members (21–23). As a second messenger molecule, cAMP participates in numerous cellular functions, physiologically and pathophysiologically (24,25). The POPDC family of proteins are a class of cAMP-binding proteins and have been reported to be involved in cancer progression and associated with prognosis in patients with cancer.…”

Amalgamation of PI3K and EZH2 blockade synergistically regulates invasion and angiogenesis: combination therapy for glioblastoma multiforme

“…Slides were dried and sealed with colorless Nail paint. Images were taken under Nikon Fluorescent Microscope (at 60X) and quantified [ 80 ].…”

“…Tube formation assay and cytokine array analysis were conducted as described previously [ 80 ]. Briefly, primary endothelial cells were cultured and incubated with conditioned media of treated and untreated cells.…”