STAT3-survivin signaling mediates a poor response to radiotherapy in HER2-positive breast cancers
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Jae-Sung Kim1,*, Hyun-Ah Kim2,*, Min-Ki Seong2, Hyesil Seol3, Jeong Su Oh4, Eun-Kyu Kim5, Jong Wook Chang6, Sang-Gu Hwang1, Woo Chul Noh2
1Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
2Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
3Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
4Department of Genetic Engineering, Sungkyunkwan University, Suwon, Korea
5Department of Surgery, Breast Cancer Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Gyeonggi-do, Korea
6Stem Cell Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
*These authors have contributed equally to this work
Jae-Sung Kim, e-mail: [email protected]
Woo Chul Noh, e-mail: [email protected]
Keywords: breast cancer, radioresistance, HER2, STAT3, survivin
Received: August 02, 2015 Accepted: January 01, 2016 Published: January 09, 2016
Although radiotherapy resistance is associated with locoregional recurrence and distant metastasis in breast cancers, clinically relevant molecular markers and critical signaling pathways of radioresistant breast cancer are yet to be defined. Herein, we show that HER2-STAT3-survivin regulation is associated with radiotherapy resistance in HER2-positive breast cancers. Depletion of HER2 by siRNA sensitized HER2-positive breast cancer cells to irradiation by decreasing STAT3 activity and survivin, a STAT3 target gene, expression in HER2-positive breast cancer cells. Furthermore, inhibition of STAT3 activation or depletion of survivin also sensitized HER2-positive breast cancer cells to irradiation, suggesting that the HER2-STAT3-survivin axis is a key pathway in radiotherapy resistance of HER2-positive breast cancer cells. In addition, our clinical analysis demonstrated the association between HER2-positive breast cancers and radiotherapy resistance. Notably, we found that increased expression of phosphorylated STAT3, STAT3, and survivin correlated with a poor response to radiotherapy in HER2-positive breast cancer tissues. These findings suggest that the HER2-STAT3-survivin axis might serve as a predictive marker and therapeutic target to overcome radiotherapy resistance in HER2-positive breast cancers.
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