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Breast Cancer Research
Published in: Breast Cancer Research 5/2012

Open Access 01-10-2012 | Research article

p130Cas/Cyclooxygenase-2 axis in the control of mesenchymal plasticity of breast cancer cells

Authors: Brigitte Bisaro, Maura Montani, Georgia Konstantinidou, Cristina Marchini, Lucia Pietrella, Manuela Iezzi, Mirco Galiè, Francesca Orso, Annalisa Camporeale, Shana M Colombo, Paola Di Stefano, Giusy Tornillo, Maria P Camacho-Leal, Emilia Turco, Daniela Taverna, Sara Cabodi, Augusto Amici, Paola Defilippi

Published in: Breast Cancer Research | Issue 5/2012

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Abstract

Introduction

Intrinsic plasticity of breast carcinoma cells allows them to undergo a transient and reversible conversion into mesenchymal cells to disseminate into distant organs, where they can re-differentiate to an epithelial-like status to form a cohesive secondary mass. The p130Cas scaffold protein is overexpressed in human ER+ and HER2+ breast cancer where it contributes to cancer progression, invasion and resistance to therapy. However, its role in regulating mesenchymal aggressive breast cancer cells remains to be determined. The aim of this study was to investigate the molecular and functional involvement of this adaptor protein in breast cancer cell plasticity.

Methods

We used silencing strategies and rescue experiments to evaluate phenotypic and biochemical changes from mesenchymal to epithelial traits in breast tumor cell lines. In the mouse A17 cell model previously related to mesenchymal cancer stem cells and basal-like breast cancer, we biochemically dissected the signaling pathways involved and performed functional in vivo tumor growth ability assays. The significance of the signaling platform was assessed in a human setting through the use of specific inhibitors in aggressive MDA-MB-231 subpopulation LM2-4175 cells. To evaluate the clinical relevance of the results, we analyzed publicly available microarray data from the Netherlands Cancer Institute and from the Koo Foundation Sun Yat-Sen Cancer Center.

Results

We show that p130Cas silencing induces loss of mesenchymal features, by downregulating Vimentin, Snail, Slug and Twist transcriptional factors, resulting in the acquirement of epithelial-like traits. Mechanistically, p130Cas controls Cyclooxygenase-2 transcriptional expression, which in turn contributes to p130Cas-dependent maintenance of mesenchymal phenotype. This cascade of events also compromises in vivo tumor growth through inhibition of cell signaling controlling cell cycle progression. c-Src and JNK kinases are sequential players in p130Cas/ Cyclooxygenase-2 axis and their pharmacological inhibition is sufficient to downregulate Cyclooxygenase-2 leading to an epithelial phenotype. Finally, in silico microarray data analysis indicates that p130Cas and Cyclooxygenase-2 concomitant overexpression predicts poor survival and high probability of breast tumor recurrence.

Conclusions

Overall, these data identify a new p130Cas/Cyclooxygenase-2 axis as a crucial element in the control of breast tumor plasticity, opening new therapeutic strategies leading to inhibition of these pathways in aggressive breast carcinoma.
Appendix
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Metadata
Title
p130Cas/Cyclooxygenase-2 axis in the control of mesenchymal plasticity of breast cancer cells
Authors
Brigitte Bisaro
Maura Montani
Georgia Konstantinidou
Cristina Marchini
Lucia Pietrella
Manuela Iezzi
Mirco Galiè
Francesca Orso
Annalisa Camporeale
Shana M Colombo
Paola Di Stefano
Giusy Tornillo
Maria P Camacho-Leal
Emilia Turco
Daniela Taverna
Sara Cabodi
Augusto Amici
Paola Defilippi
Publication date
01-10-2012
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 5/2012
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3342

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