STAT3-survivin signaling mediates a poor response to radiotherapy in HER2-positive breast cancers.

Abstract

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.

• Authors: Jae-Sung Kim, Hyun-Ah Kim, Min-Ki Seong, Hyesil Seol, Jeong Su Oh, Eun-Kyu Kim, Jong Wook Chang, Sang-Gu Hwang, Woo Chul Noh
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 6 Pg. 7055-65 (Feb 09 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26755645 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• RNA, Small Interfering
• Receptors, Estrogen
• Receptors, Progesterone
• STAT3 Transcription Factor
• Survivin
• Receptor, ErbB-2

Topics

• Apoptosis
• Blotting, Western
• Breast Neoplasms (metabolism, pathology, radiotherapy)
• Case-Control Studies
• Cell Proliferation
• Female
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic (radiation effects)
• Humans
• Immunoenzyme Techniques
• Inhibitor of Apoptosis Proteins (antagonists & inhibitors, genetics, metabolism)
• Middle Aged
• Neoplasm Recurrence, Local (metabolism, pathology, radiotherapy)
• Neoplasm Staging
• Phosphorylation (radiation effects)
• Prognosis
• RNA, Small Interfering (genetics)
• Radiation Tolerance
• Radiotherapy, Adjuvant (adverse effects)
• Receptor, ErbB-2 (antagonists & inhibitors, genetics, metabolism)
• Receptors, Estrogen (metabolism)
• Receptors, Progesterone (metabolism)
• Retrospective Studies
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Survival Rate
• Survivin
• Tumor Cells, Cultured