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

Oncogene volume 34, pages 2189–2203 (2015)Cite this article

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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.

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Acknowledgements

We thank Agnes Viale and Russell Towers for technical assistance. We are indebted to Joan Massague (Memorial Sloan-Kettering Cancer Center) for generously providing cell lines and some constructs. We are grateful to the entire Tumour Procurement Service at MSKCC for facilitating tissue procurement and contributing valuable input. This work was supported by grants from the Department of Defense (DOD) (grant no. BC120568), the Frederick Adler Fund, the Avon Foundation, the Elsa Pardee foundation, the MSKCC Metastasis Center and the STARR Cancer Consortium (all to TAC). LAW was supported by The Canadian Institutes of Health Research PDF Award MFE-127325. DMR was supported by the HHMI Research Fellows Program and NIH MSTP grant T32GM007739. AS was supported by the Ruth L. Kirschstein National Research Award (NRSA) number T32CA009512 from the National Cancer Institute. ST was supported by an NIH T32 grant (5T32CA160001).

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Authors and Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    L A Walsh, D M Roy, A Snyder, S Turcan & T A Chan

  2. Weill Cornell Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY, USA

    D M Roy

  3. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    M Reyngold & T A Chan

  4. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    D Giri

  5. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    A Snyder & J Bromberg

  6. Weill Graduate School of Medical Sciences, New York, NY, USA

    C R Badwe

  7. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    J Lyman & T A King

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  1. L A Walsh
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Walsh, L., Roy, D., Reyngold, M. et al. RECK controls breast cancer metastasis by modulating a convergent, STAT3-dependent neoangiogenic switch. Oncogene 34, 2189–2203 (2015). https://doi.org/10.1038/onc.2014.175

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