RB Loss Promotes Prostate Cancer Metastasis

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...

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Veröffentlicht in:	Cancer research (Chicago, Ill.) Jg. 77; H. 4; S. 982
Hauptverfasser:	Thangavel, Chellappagounder, Boopathi, Ettickan, Liu, Yi, Haber, Alex, Ertel, Adam, Bhardwaj, Anshul, Addya, Sankar, Williams, Noelle, Ciment, Stephen J, Cotzia, Paolo, Dean, Jeffry L, Snook, Adam, McNair, Chris, Price, Matt, Hernandez, James R, Zhao, Shuang G, Birbe, Ruth, McCarthy, James B, Turley, Eva A, Pienta, Kenneth J, Feng, Felix Y, Dicker, Adam P, Knudsen, Karen E, Den, Robert B
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 15.02.2017
Schlagworte:	Actins - metabolism Animals Cell Line, Tumor Cyclin-Dependent Kinase 4 - antagonists & inhibitors Cyclin-Dependent Kinase 6 - antagonists & inhibitors E2F Transcription Factors - physiology Extracellular Matrix Proteins - antagonists & inhibitors Extracellular Matrix Proteins - genetics Extracellular Matrix Proteins - physiology Humans Hyaluronan Receptors - genetics Hyaluronan Receptors - physiology Male Mice Neoplasm Metastasis Prostatic Neoplasms - pathology Retinoblastoma Protein - physiology rho-Associated Kinases - physiology Signal Transduction - physiology
ISSN:	1538-7445, 1538-7445
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Zusammenfassung:	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. .
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1538-7445 1538-7445
DOI:	10.1158/0008-5472.CAN-16-1589