Journal
ONCOTARGET
Volume 7, Issue 6, Pages 7055-7065Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6855
Keywords
breast cancer; radioresistance; HER2; STAT3; survivin
Categories
Funding
- Radiological Translational Research Program [50451-2015]
- Korean Health Technology R&D Project, Ministry of Health Welfare [HI14C1864]
- National R&D Program of the Korea Institute of Radiological and Medical Sciences - Ministry of Science, ICT & Future Planning [1711021781]
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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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