title: RB Loss Promotes Prostate Cancer Metastasis.
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.
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Chellappagounder
authors.initials: C
authors.lastname: Thangavel
authors.affiliation: Sidney Kimmel Center for Translation Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Ettickan
authors.initials: E
authors.lastname: Boopathi
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Alex
authors.initials: A
authors.lastname: Haber
authors.affiliation: Cancer Genomics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.|Sidney Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.affiliation: Department of Biochemistry and Molecular Biology, X-ray Crystallography and Molecular Interactions, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Anshul
authors.initials: A
authors.lastname: Bhardwaj
authors.affiliation: Cancer Genomics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.|Sidney Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Sankar
authors.initials: S
authors.lastname: Addya
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Noelle
authors.initials: N
authors.lastname: Williams
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ciment
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cotzia
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Jeffry L
authors.initials: JL
authors.lastname: Dean
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Adam
authors.initials: A
authors.lastname: Snook
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Chris
authors.initials: C
authors.lastname: McNair
authors.affiliation: Department of Laboratory of Medicine and Pathology, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota.
authors.forename: Matt
authors.initials: M
authors.lastname: Price
authors.affiliation: Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland.
authors.forename: James R
authors.initials: JR
authors.lastname: Hernandez
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Shuang G
authors.initials: SG
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Ruth
authors.initials: R
authors.lastname: Birbe
authors.affiliation: Department of Laboratory of Medicine and Pathology, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota.
authors.forename: James B
authors.initials: JB
authors.lastname: McCarthy
authors.affiliation: London Health Sciences Center, Departments of Oncology, Biochemistry and Surgery, Schulich School of Medicine, Western University, London, Ontario, Canada.
authors.forename: Eva A
authors.initials: EA
authors.lastname: Turley
authors.affiliation: Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.|Sidney Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.|Sidney Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.|Department of Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.|Department of Urology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania. robert.den@jefferson.edu.|Sidney Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.|Department of Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.|Department of Urology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Den
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D050684:E2F Transcription Factors / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D054460:rho-Associated Kinases / Q000502:physiology
chemical_list: D000199:Actins; D050684:E2F Transcription Factors; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D016160:Retinoblastoma Protein; C098946:hyaluronan-mediated motility receptor; D054460:rho-Associated Kinases; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6