title: 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.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Hyun-Ah
authors.initials: HA
authors.lastname: Kim
authors.affiliation: Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Min-Ki
authors.initials: MK
authors.lastname: Seong
authors.affiliation: Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Hyesil
authors.initials: H
authors.lastname: Seol
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon, Korea.
authors.forename: Jeong Su
authors.initials: JS
authors.lastname: Oh
authors.affiliation: Department of Surgery, Breast Cancer Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Gyeonggi-do, Korea.
authors.forename: Eun-Kyu
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Stem Cell Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.
authors.forename: Jong Wook
authors.initials: JW
authors.lastname: Chang
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.affiliation: Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Woo Chul
authors.initials: WC
authors.lastname: Noh
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D016022:Case-Control Studies; D049109:Cell Proliferation; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D009367:Neoplasm Staging; D010766:Phosphorylation / Q000528:radiation effects; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D000077022:Survivin; D014407:Tumor Cells, Cultured
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D050796:STAT3 Transcription Factor; D000077022:Survivin; C107489:BIRC5 protein, human
keywords: HER2; STAT3; breast cancer; radioresistance; survivin