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ABSTRACT The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology. Comparing gene expression in isogenic

androgen-dependent and CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was also elevated in primary and metastatic tumors of individuals with CRPC. Ectopic

expression of N-cadherin in nonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion and metastasis. Monoclonal antibodies against the ectodomain of

N-cadherin reduced proliferation, adhesion and invasion of prostate cancer cells _in vitro_. _In vivo_, these antibodies slowed the growth of multiple established CRPC xenografts, blocked

local invasion and metastasis and, at higher doses, led to complete regression. N-cadherin–specific antibodies markedly delayed the time to emergence of castration resistance, markedly

affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion. These data indicate that N-cadherin is a major

cause of both prostate cancer metastasis and castration resistance. Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit. Access through

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CONTENT BEING VIEWED BY OTHERS ANDROGEN RECEPTOR-INDUCED INTEGRIN Α6Β1 AND BNIP3 PROMOTE SURVIVAL AND RESISTANCE TO PI3K INHIBITORS IN CASTRATION-RESISTANT PROSTATE CANCER Article 21 June

2020 LOSS AND REVIVAL OF ANDROGEN RECEPTOR SIGNALING IN ADVANCED PROSTATE CANCER Article Open access 08 January 2021 ANDROGEN RECEPTOR MONOMERS AND DIMERS REGULATE OPPOSING BIOLOGICAL

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Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported in parts by the US National Cancer Institute Prostate Cancer SPORE at the University of California–Los Angeles

(P50CA092131-09 to R.E.R.), US Department of Defense Prostate Cancer Research grants (W81XWH-06-1-0324 to Z.A.W., W81XWH-09-1-0630 to R.E.R. and M.B.R., PC061456 to J.H.), Takeda

Pharmaceuticals, the Jean Perkins Foundation and the American Cancer Society (RSG-07-092-01-TBE to J.H.). We also thank S. and L. Resnick, the Prostate Cancer Foundation and the Luskin

Foundation for generous support and J. Said and N. Doan for immunohistochemical assessments. LNCaP-CL1 cells were provided by C.L. Tso (University of California–Los Angeles). Plasmid pΔVPR

was provided by I. Chen (University of California–Los Angeles). AUTHOR INFORMATION Author notes * Hiroshi Tanaka and Evelyn Kono: These authors contributed equally to this work. AUTHORS AND

AFFILIATIONS * Department of Urology, Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California, USA Hiroshi Tanaka, Evelyn Kono, Chau P Tran, Joyce Yamashiro,

 Tatsuya Shimomura, Robert Wada, Jaibin An, Matthew B Rettig & Robert E Reiter * Jonsson Comprehensive Cancer Center, Geffen School of Medicine, University of California–Los Angeles, Los

Angeles, California, USA Hiroshi Tanaka, Evelyn Kono, Chau P Tran, Joyce Yamashiro, Tatsuya Shimomura, Jiaoti Huang, Matthew B Rettig, Zev A Wainberg & Robert E Reiter * Department of

Urology, University of Tokyo, Tokyo, Japan Hideyo Miyazaki * Vancouver Prostate Center, University of British Columbia, Vancouver, British Columbia, Canada Ladan Fazli & Martin Gleave *

Department of Pathology, Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California, USA Jiaoti Huang * Department of Urology, University of Washington Medical

Center, Puget Sound Veterans Health Care Administration, Seattle, Washington, USA Robert L Vessella * Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System–West Los

Angeles, Los Angeles, California, USA Jaibin An & Matthew B Rettig * Department of Human Genetics, David Geffen School of Medicine, University of California–Los Angeles, Los Angeles,

California, USA Steven Horvath * Department of Biostatistics, School of Public Health, University of California–Los Angeles, Los Angeles, California, USA Steven Horvath * Division of

Hematology and Oncology, Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California, USA Zev A Wainberg * Molecular Biology Institute, Geffen School of

Medicine, University of California–Los Angeles, Los Angeles, California, USA Robert E Reiter Authors * Hiroshi Tanaka View author publications You can also search for this author inPubMed 

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can also search for this author inPubMed Google Scholar * Robert Wada View author publications You can also search for this author inPubMed Google Scholar * Jiaoti Huang View author

publications You can also search for this author inPubMed Google Scholar * Robert L Vessella View author publications You can also search for this author inPubMed Google Scholar * Jaibin An

View author publications You can also search for this author inPubMed Google Scholar * Steven Horvath View author publications You can also search for this author inPubMed Google Scholar *

Martin Gleave View author publications You can also search for this author inPubMed Google Scholar * Matthew B Rettig View author publications You can also search for this author inPubMed 

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author inPubMed Google Scholar CONTRIBUTIONS H.T. and E.K. designed and conducted _in vitro_ and _in vivo_ studies. C.P.T. generated stable N-cadherin–knockdown reagents and prepared the

manuscript. H.M. made the N-cadherin–overexpressing cell lines. J.Y. and R.W. performed gene and protein expression analyses. T.S. contributed to the _in vivo_ N-cadherin–knockdown and

antibody studies. F.L. and M.G. conducted immunohistochemical evaluation of prostate cancer specimens. J.H. contributed to immunohistochemical analyses of _in vivo_ studies. R.L.V. provided

clinical materials for the initial N-cadherin screening in metastases. J.A. and M.B.R. provided data on AKT activity. S.H. performed gene expression analysis for stem cell markers. Z.A.W.

generated the monoclonal antibodies. R.E.R. conceived of the study and supervised the project. All authors discussed the results and commented on the manuscript at all stages. CORRESPONDING

AUTHOR Correspondence to Robert E Reiter. ETHICS DECLARATIONS COMPETING INTERESTS R.E.R. has an equity interest in EMTx Therapeutics, which has an option to license and develop

N-cadherin–specific antibodies for cancer therapy. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Figures 1–6 (PDF 1282 kb) RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Tanaka, H., Kono, E., Tran, C. _et al._ Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and

castration resistance. _Nat Med_ 16, 1414–1420 (2010). https://doi.org/10.1038/nm.2236 Download citation * Received: 16 April 2010 * Accepted: 09 September 2010 * Published: 07 November 2010

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