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

   

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.
Article Title:	RECK controls breast cancer metastasis by modulating a convergent, STAT3-dependent neoangiogenic switch
Abstract:	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. © 2015 Macmillan Publishers Limited All rights reserved.
Journal Title:	Oncogene
Volume:	34
Issue:	17
ISSN:	0950-9232
Publisher:	Nature Publishing Group
Date Published:	2015-04-23
Start Page:	2189
End Page:	2203
Language:	English
DOI:	10.1038/onc.2014.175
PROVIDER:	scopus
PMCID:	PMC4344427
PUBMED:	24931164
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84939889685&partnerID=40&md5=2d2be8966b1350ea1f6e488945cf84a4
Notes:	Export Date: 2 September 2015 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/79896