Research Papers:
RHAMM splice variants confer radiosensitivity in human breast cancer cell lines
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Abstract
Alexandra Schütze1, Christian Vogeley1, Tobias Gorges2, Sören Twarock1, Jonas Butschan1, Anna Babayan2, Diana Klein3, Shirley K. Knauer4, Eric Metzen5, Volkmar Müller6, Verena Jendrossek3, Klaus Pantel2, Karin Milde-Langosch6, Jens W. Fischer1,*, Katharina Röck1,*
1Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany
2Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
3Institute of Cell Biology (Cancer Research), University Hospital, University of Duisburg-Essen, Essen, Germany
4Institute for Molecular Biology II, Centre for Medical Biotechnology (ZMB), University of Duisburg-Essen, Essen, Germany
5Institute of Physiology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany
6Department of Gynecology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
*These authors have contributed equally to this work
Correspondence to:
Jens W. Fischer, e-mail: [email protected]
Keywords: breast cancer, ionizing radiation, RHAMM, cell death, extracellular matrix
Received: September 29, 2015 Accepted: January 20, 2016 Published: February 8, 2016
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.
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