RECK controls breast cancer metastasis by modulating a convergent, STAT3-dependent neoangiogenic switch

Metastasis is the primary cause of cancer-related death in oncology patients. A comprehensive understanding of the molecular mechanisms that cancer cells usurp to promote metastatic dissemination is critical for the development and implementation of novel diagnostic and treatment strategies. Here we...

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Bibliographic Details
Published in:	Oncogene Vol. 34; no. 17; pp. 2189 - 2203
Main Authors:	Walsh, L A, Roy, D M, Reyngold, M, Giri, D, Snyder, A, Turcan, S, Badwe, C R, Lyman, J, Bromberg, J, King, T A, Chan, T A
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 23-04-2015 Nature Publishing Group
Subjects:	631/67/1347 631/67/322 631/80/86 Angiogenesis Animal models Animals Apoptosis Breast cancer Breast Neoplasms - blood supply Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer metastasis Cell Biology Cell surface Cellular biology Complications and side effects Cytokines Female Genetic aspects GPI-Linked Proteins - genetics GPI-Linked Proteins - metabolism Human Genetics Humans Internal Medicine Medicine Medicine & Public Health Membrane proteins Membranes Metastases Metastasis Mice Mice, Nude Molecular modelling Neoplasm Metastasis Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Neovascularization, Pathologic - genetics Neovascularization, Pathologic - metabolism Neovascularization, Pathologic - pathology Oncology original-article Phenotypes Properties Proteins Reversion Stat3 protein STAT3 Transcription Factor U-Plasminogen activator Urokinase-Type Plasminogen Activator - genetics Urokinase-Type Plasminogen Activator - metabolism Vascular endothelial growth factor Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - metabolism Xenografts
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Summary:	Metastasis is the primary cause of cancer-related death in oncology patients. A comprehensive understanding of the molecular mechanisms that cancer cells usurp to promote metastatic dissemination is critical for the development and implementation of novel diagnostic and treatment strategies. Here we show that the membrane protein RECK (Reversion-inducing cysteine-rich protein with kazal motifs) controls breast cancer metastasis by modulating a novel, non-canonical and convergent signal transducer and activator of transcription factor 3 (STAT3)-dependent angiogenic program. Neoangiogenesis and STAT3 hyperactivation are known to be fundamentally important for metastasis, but the root molecular initiators of these phenotypes are poorly understood. Our study identifies loss of RECK as a critical and previously unknown trigger for these hallmarks of metastasis. Using multiple xenograft mouse models, we comprehensively show that RECK inhibits metastasis, concomitant with a suppression of neoangiogenesis at secondary sites, while leaving primary tumor growth unaffected. Further, with functional genomics and biochemical dissection we demonstrate that RECK controls this angiogenic rheostat through a novel complex with cell surface receptors to regulate STAT3 activation, cytokine signaling, and the induction of both vascular endothelial growth factor and urokinase plasminogen activator. In accordance with these findings, inhibition of STAT3 can rescue this phenotype both in vitro and in vivo . Taken together, our study uncovers, for the first time, that RECK is a novel regulator of multiple well-established and robust mediators of metastasis; thus, RECK is a keystone protein that may be exploited in a clinical setting to target metastatic disease from multiple angles.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2014.175