EPCR promotes breast cancer progression by altering SPOCK1/testican 1-mediated 3D growth

Perurena, N., Zandueta, C., Martinez-Canarias, S., Moreno, H., Vicent, S., Almeida, A. S., Guruceaga, E., Gomis, R. R., Santisteban, M., Egeblad, M., Hermida, J., Lecanda, F. (January 2017) EPCR promotes breast cancer progression by altering SPOCK1/testican 1-mediated 3D growth. J Hematol Oncol, 10 (1). p. 23. ISSN 1756-8722 (Electronic)1756-8722 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/28103946
DOI: 10.1186/s13045-017-0399-x

Abstract

BACKGROUND: Activated protein C/endothelial protein C receptor (APC/EPCR) axis is physiologically involved in anticoagulant and cytoprotective activities in endothelial cells. Emerging evidence indicates that EPCR also plays a role in breast stemness and human tumorigenesis. Yet, its contribution to breast cancer progression and metastasis has not been elucidated. METHODS: Transcriptomic status of EPCR was examined in a cohort of 286 breast cancer patients. Cell growth kinetics was evaluated in control and EPCR and SPARC/osteonectin, Cwcv, and kazal-like domains proteoglycan (SPOCK1/testican 1) silenced breast cancer cells in 2D, 3D, and in co-culture conditions. Orthotopic tumor growth and lung and osseous metastases were evaluated in several human and murine xenograft breast cancer models. Tumor-stroma interactions were further studied in vivo by immunohistochemistry and flow cytometry. An EPCR-induced gene signature was identified by microarray analysis. RESULTS: Analysis of a cohort of breast cancer patients revealed an association of high EPCR levels with adverse clinical outcome. Interestingly, EPCR knockdown did not affect cell growth kinetics in 2D but significantly reduced cell growth in 3D cultures. Using several human and murine xenograft breast cancer models, we showed that EPCR silencing reduced primary tumor growth and secondary outgrowths at metastatic sites, including the skeleton and the lungs. Interestingly, these effects were independent of APC ligand stimulation in vitro and in vivo. Transcriptomic analysis of EPCR-silenced tumors unveiled an effect mediated by matricellular secreted proteoglycan SPOCK1/testican 1. Interestingly, SPOCK1 silencing suppressed in vitro 3D growth. Moreover, SPOCK1 ablation severely decreased orthotopic tumor growth and reduced bone metastatic osteolytic tumors. High SPOCK1 levels were also associated with poor clinical outcome in a subset breast cancer patients. Our results suggest that EPCR through SPOCK1 confers a cell growth advantage in 3D promoting breast tumorigenesis and metastasis. CONCLUSIONS: EPCR represents a clinically relevant factor associated with poor outcome and a novel vulnerability to develop combination therapies for breast cancer patients.

Item Type: Paper
Uncontrolled Keywords: Extracellular matrix Matricellular Metastasis Microenvironment Sphere cultures
Subjects: diseases & disorders > cancer > cancer types > breast cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > extracellular matrix proteins
diseases & disorders > cancer > metastasis
diseases & disorders > cancer > drugs and therapies > tumor microenvironment
CSHL Authors:
Communities: CSHL labs > Egeblad lab
Depositing User: Matt Covey
Date: 19 January 2017
Date Deposited: 25 Jan 2017 21:42
Last Modified: 07 Mar 2018 15:02
PMCID: PMC5248526
Related URLs:
URI: http://repository.cshl.edu/id/eprint/34049

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