Abstract
RB loss occurs commonly in neoplasia but its contributions to advanced cancer have not been assessed directly. Here we show that RB loss in multiple murine models of cancer produces a prometastatic phenotype. Gene expression analyses showed that regulation of the cell motility receptor RHAMM by the RB/E2F pathway was critical for epithelial-mesenchymal transition, motility, and invasion by cancer cells. Genetic modulation or pharmacologic inhibition of RHAMM activity was sufficient and necessary for metastatic phenotypes induced by RB loss in prostate cancer. Mechanistic studies in this setting established that RHAMM stabilized F-actin polymerization by controlling ROCK signaling. Collectively, our findings show how RB loss drives metastatic capacity and highlight RHAMM as a candidate therapeutic target for treating advanced prostate cancer. Cancer Res; 77(4); 982-95. ©2016 AACR.
©2016 American Association for Cancer Research.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Actins / metabolism
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Animals
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Cell Line, Tumor
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors
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Cyclin-Dependent Kinase 6 / antagonists & inhibitors
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E2F Transcription Factors / physiology
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Extracellular Matrix Proteins / antagonists & inhibitors
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Extracellular Matrix Proteins / genetics
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Extracellular Matrix Proteins / physiology
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Humans
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / physiology
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Male
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Mice
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Neoplasm Metastasis
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Prostatic Neoplasms / pathology*
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Retinoblastoma Protein / physiology*
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Signal Transduction / physiology
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rho-Associated Kinases / physiology
Substances
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Actins
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E2F Transcription Factors
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Extracellular Matrix Proteins
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Hyaluronan Receptors
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Retinoblastoma Protein
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hyaluronan-mediated motility receptor
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rho-Associated Kinases
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6