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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Walsh
authors.affiliation: 1] Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Weill Cornell Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Roy
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Reyngold
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Giri
authors.affiliation: 1] Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Snyder
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Turcan
authors.affiliation: Weill Graduate School of Medical Sciences, New York, NY, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Badwe
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lyman
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bromberg
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: King
authors.affiliation: 1] Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Chan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; C115460:RECK protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014568:Urokinase-Type Plasminogen Activator