Title | RECK controls breast cancer metastasis by modulating a convergent, STAT3-dependent neoangiogenic switch. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Walsh LA, Roy DM, Reyngold M, Giri D, Snyder A, Turcan S, Badwe CR, Lyman J, Bromberg J, King TA, Chan TA |
Journal | Oncogene |
Volume | 34 |
Issue | 17 |
Pagination | 2189-203 |
Date Published | 2015 Apr 23 |
ISSN | 1476-5594 |
Keywords | Animals, Breast Neoplasms, Female, GPI-Linked Proteins, Humans, Mice, Mice, Nude, Neoplasm Metastasis, Neoplasm Proteins, Neovascularization, Pathologic, STAT3 Transcription Factor, Urokinase-Type Plasminogen Activator, Vascular Endothelial Growth Factor A |
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. |
DOI | 10.1038/onc.2014.175 |
Alternate Journal | Oncogene |
PubMed ID | 24931164 |
PubMed Central ID | PMC4344427 |
Grant List | T32 CA160001 / CA / NCI NIH HHS / United States T32 CA009512 / CA / NCI NIH HHS / United States MFE-127325 / / Canadian Institutes of Health Research / Canada T32GM007739 / GM / NIGMS NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:11pm