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

Overview of attention for article published in Breast Cancer Research, October 2012
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Title
p130Cas/Cyclooxygenase-2 axis in the control of mesenchymal plasticity of breast cancer cells
Published in
Breast Cancer Research, October 2012
DOI 10.1186/bcr3342
Pubmed ID
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

Abstract

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.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 26 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 26 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 8 31%
Professor 3 12%
Student > Bachelor 3 12%
Student > Ph. D. Student 3 12%
Student > Master 2 8%
Other 4 15%
Unknown 3 12%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 9 35%
Agricultural and Biological Sciences 7 27%
Medicine and Dentistry 5 19%
Environmental Science 1 4%
Computer Science 1 4%
Other 1 4%
Unknown 2 8%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 04 November 2012.
All research outputs
#20,655,488
of 25,371,288 outputs
Outputs from Breast Cancer Research
#1,705
of 2,052 outputs
Outputs of similar age
#158,188
of 201,993 outputs
Outputs of similar age from Breast Cancer Research
#29
of 41 outputs
Altmetric has tracked 25,371,288 research outputs across all sources so far. This one is in the 10th percentile – i.e., 10% of other outputs scored the same or lower than it.
So far Altmetric has tracked 2,052 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 12.2. This one is in the 8th percentile – i.e., 8% of its peers scored the same or lower than it.
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We're also able to compare this research output to 41 others from the same source and published within six weeks on either side of this one. This one is in the 19th percentile – i.e., 19% of its contemporaries scored the same or lower than it.