RHAMM splice variants confer radiosensitivity in human breast cancer cell lines
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RHAMM splice variants confer radiosensitivity in human breast cancer cell lines. / Schütze, Alexandra; Vogeley, Christian; Gorges, Tobias; Twarock, Sören; Butschan, Jonas; Babayan, Anna; Klein, Diana; Knauer, Shirley K; Metzen, Eric; Müller, Volkmar; Jendrossek, Verena; Pantel, Klaus; Milde-Langosch, Karin; Fischer, Jens W; Röck, Katharina.
In: ONCOTARGET, Vol. 7, No. 16, 08.02.2016, p. 21428-40.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - RHAMM splice variants confer radiosensitivity in human breast cancer cell lines
AU - Schütze, Alexandra
AU - Vogeley, Christian
AU - Gorges, Tobias
AU - Twarock, Sören
AU - Butschan, Jonas
AU - Babayan, Anna
AU - Klein, Diana
AU - Knauer, Shirley K
AU - Metzen, Eric
AU - Müller, Volkmar
AU - Jendrossek, Verena
AU - Pantel, Klaus
AU - Milde-Langosch, Karin
AU - Fischer, Jens W
AU - Röck, Katharina
PY - 2016/2/8
Y1 - 2016/2/8
N2 - 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.
AB - 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.
U2 - 10.18632/oncotarget.7258
DO - 10.18632/oncotarget.7258
M3 - SCORING: Journal article
C2 - 26870892
VL - 7
SP - 21428
EP - 21440
JO - ONCOTARGET
JF - ONCOTARGET
SN - 1949-2553
IS - 16
ER -