title: RHAMM splice variants confer radiosensitivity in human breast cancer cell lines.
abstract: Biomarkers for prognosis in radiotherapy-treated breast cancer patients are urgently needed and important to stratify patients for adjuvant therapies. Recently, a role of the receptor of hyaluronan-mediated motility (RHAMM) has been suggested for tumor progression. Our aim was (i) to investigate the prognostic value of RHAMM in breast cancer and (ii) to unravel its potential function in the radiosusceptibility of breast cancer cells. We demonstrate that RHAMM mRNA expression in breast cancer biopsies is inversely correlated with tumor grade and overall survival. Radiosusceptibility in vitro was evaluated by sub-G1 analysis (apoptosis) and determination of the proliferation rate. The potential role of RHAMM was addressed by short interfering RNAs against RHAMM and its splice variants. High expression of RHAMMv1/v2 in p53 wild type cells (MCF-7) induced cellular apoptosis in response to ionizing radiation. In comparison, in p53 mutated cells (MDA-MB-231) RHAMMv1/v2 was expressed sparsely resulting in resistance towards irradiation induced apoptosis. Proliferation capacity was not altered by ionizing radiation in both cell lines. Importantly, pharmacological inhibition of the major ligand of RHAMM, hyaluronan, sensitized both cell lines towards radiation induced cell death. Based on the present data, we conclude that the detection of RHAMM splice variants in correlation with the p53 mutation status could help to predict the susceptibility of breast cancer cells to radiotherapy. Additionally, our studies raise the possibility that the response to radiotherapy in selected cohorts may be improved by pharmaceutical strategies against RHAMM and its ligand hyaluronan.
authors: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors: Alexandra
authors: A
authors: Schütze
authors: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors: Christian
authors: C
authors: Vogeley
authors: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Tobias
authors: T
authors: Gorges
authors: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors: Sören
authors: S
authors: Twarock
authors: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors: Jonas
authors: J
authors: Butschan
authors: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Anna
authors: A
authors: Babayan
authors: Institute of Cell Biology (Cancer Research), University Hospital, University of Duisburg-Essen, Essen, Germany.
authors: Diana
authors: D
authors: Klein
authors: Institute for Molecular Biology II, Centre for Medical Biotechnology (ZMB), University of Duisburg-Essen, Essen, Germany.
authors: Shirley K
authors: SK
authors: Knauer
authors: Institute of Physiology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.
authors: Eric
authors: E
authors: Metzen
authors: Department of Gynecology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors: Volkmar
authors: V
authors: Müller
authors: Institute of Cell Biology (Cancer Research), University Hospital, University of Duisburg-Essen, Essen, Germany.
authors: Verena
authors: V
authors: Jendrossek
authors: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Klaus
authors: K
authors: Pantel
authors: Department of Gynecology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors: Karin
authors: K
authors: Milde-Langosch
authors: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors: Jens W
authors: JW
authors: Fischer
authors: Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors: Katharina
authors: K
authors: Röck
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics* / Q000528:radiation effects; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D061986:MCF-7 Cells; D011379:Prognosis; D034622:RNA Interference; D012326:RNA Splicing; D011836:Radiation Tolerance / Q000235:genetics; D011839:Radiation, Ionizing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C098946:hyaluronan-mediated motility receptor
keywords: RHAMM; breast cancer; cell death; extracellular matrix; ionizing radiation