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

Kim, Jae-Sung; Kim, Hyun-Ah; Seong, Min-Ki; Seol, Hyesil; Oh, Jeong Su; Kim, Eun‐Kyu; Chang, Jong Wook; Hwang, Sang‐Gu; Noh, Woo Chul

doi:10.18632/oncotarget.6855

Cited by 56 publications

(47 citation statements)

References 42 publications

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“…HER2 protein overexpression has often been found in clinical breast cancer patients, and the clinical manifestations of such patients are exceptionally poor, including higher degrees of malignancy, strong metastatic ability and clinically low patient survival (9). In addition, it has been reported that radiation resistance often occurs when treating HER2-positive breast cancer patients in clinic (10), which greatly influences radiation therapy. However, at present, few studies have investigated the mechanism involved in the radiosensitivity of HER2-positive breast cancer patients.…”

Section: Introductionmentioning

confidence: 99%

ZEB1 is involved in regulating HER2-positive breast cancer radiosensitivity by controlling EMT

Han

Zhu

et al. 2018

Oncol Lett

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Abstract. Breast cancer is a malignant tumor that can rapidly progress to cancer for which there are limited therapeutic options. The aim of the present study was to examine the regulatory mechanism of human epidermal growth factor receptor 2 (HER2)-positive breast cancer radiosensitivity by comparing the protein expression levels of HER2 in breast cancer cell lines. Breast cancer cell line MCF-7 (low HER2 expression) and breast cancer cell lines ZR-7530 and SK-BR-3 (high HER2 expression) were selected for the present study. The cell lines were treated with shRNA and different doses of radiation (2,4 and 6 Gy). Immunohistochemistry was performed on HER2-positive breast cancer tissues to detect the protein and mRNA expression levels of ZEB1 and HER2. A Transwell assay was performed to determine changes in the invasion capacity of cells under the different treatments. Western blot analysis was performed to detect the changes in ZEB1 and E-cadherin protein levels, and qPCR was performed to detect the mRNA and protein expression levels of HER2, ZEB1 and E-cadherin. Furthermore, immunohistochemistry was performed in tissues to detect the protein levels of HER2, ZEB1 and E-cadherin, and determine their correlation. The results showed that, ZEB1 protein and mRNA levels were higher in ZR-7530 and SK-BR-3 cells with a high HER2 expression compared to that in MCF-7 lines with a low HER2 expression. After 0,2,4 and 6 Gy of radiation treatments, the cell invasion inhibitory rate in the no-load control group was 0.00, 18.70, 31.24 and 47.66%, respectively, while the cell invasion inhibitory rate in the shRNA group was 0.00, 25.32, 40.71 and 58.46%, respectively. Compared with the no-load control group, the cell invasion inhibitory rate was higher in the treatment group, and the difference was statistically significant (P<0.05). Furthermore, the protein and mRNA levels of E-cadherin increased after HER2 knockdown treatment. Based on the Student's t-test analysis, the difference was statistically significant (P<0.05). Pearson's analysis revealed that HER2 protein levels were positively correlated with ZEB1 protein levels (r=0.480, P=0.013), but was negatively correlated with E-cadherin protein levels (r=-0.650, P=0.000). Therefore, ZEB1 protein can affect HER2-positive breast cancer cell epithelial-mesenchymal transition progression, and is involved in regulating cell radiosensitivity. This finding suggests that ZEB1 is a potential target protein that can be used as a clinical inhibitor for changes in HER2-positive breast cancer radiation sensitivity.

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Section: Introductionmentioning

confidence: 99%

ZEB1 is involved in regulating HER2-positive breast cancer radiosensitivity by controlling EMT

Han

Zhu

et al. 2018

Oncol Lett

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“…We also identified Stat3 as the major target of miR-124. It has been shown that STAT3-survivin signaling mediated a poor response to radiotherapy in HER2-positive breast cancers (15). We thus hypothesized that weakly expressed miR-124 might enhance Stat3 expression and activity, contributing to radiotherapy resistance in these cells.…”

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confidence: 99%

MicroRNA-124 enhances response to radiotherapy in human epidermal growth factor receptor 2-positive breast cancer cells by targeting signal transducer and activator of transcription 3

Xiong

2016

Croat Med J

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AimTo determine whether microRNA (miR)-124 enhances the response to radiotherapy in human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells by targeting signal transducer and activator of transcription 3 (Stat3).MethodsmiR-29b expression was measured in 80 pairs of breast tumor samples and adjacent normal tissues collected between January 2013 and July 2014. Activity changes of 50 canonical signaling pathways upon miR-124 overexpression were determined using Cignal Signal Transduction Reporter Array. Target gene of miR-124 was determined using Targetscan and validated by Western blotting and dual-luciferase assay. Cell death rate was assessed by propidium iodide (PI)/ Annexin V staining followed by flow cytometry analysis. Stat3 and miR-124 expression was further measured in 10 relapsed (non-responder) and 10 recurrence-free HER2-positive breast cancer patients.ResultsMiR-124 expression was down-regulated in HER2 positive breast cancers compared with normal tissues, and was negatively associated with tumor size. MiR-124 overexpression in HER2 positive breast cancer cell line SKBR3 significantly reduced the activity of Stat3 signaling pathway compared with control transfection (P < 0.001). Bioinformatic prediction and function assay suggested that miR-124 directly targeted Stat3, which is a key regulator of HER2 expression. MiR-124 overexpression down-regulated Stat3 and potently enhanced cell death upon irradiation. Consistently, chemical inhibitor of Stat3 also sensitized HER2-positive breast cancer cells to irradiation. Moreover, increased Stat3 expression and reduced miR-124 expression were associated with a poor response to radiotherapy in HER2-positive breast cancers.ConclusionsWeak miR-124 expression might enhance Stat3 expression and radiotherapy resistance in HER2-positive breast cancer cells.

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“…One of the most common types of breast cancer is ErBb2/HER2-positive breast cancer, which accounts for 25% -30% of all cases of breast cancer (23). ErbB2 protein is expressed at high levels on the surface of ErBb2-positive breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Selection and Evaluation of Human Recombinant Antibodies against ErbB2 Antigen for Breast Cancer Immunotherapy

Nadimi

Nejatollahi

2017

Shiraz E-Med J

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Background: Breast cancer is the most common cause of cancer-related death in women worldwide. ErBb2/HER2 breast cancer accounts for 25% -30% of all cases of breast cancer. Approved anti-ErbB2 monoclonal antibodies, trastuzumab and pertuzumab, are currently used for the treatment of ErbB-positive breast cancer, although their clinical use is limited due to their immunogenicity. Human recombinant single-chain antibodies, which are produced by antibody engineering technologies, are new and effective antibodies in cancer immunotherapy.

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

Cited by 56 publications

References 42 publications

ZEB1 is involved in regulating HER2-positive breast cancer radiosensitivity by controlling EMT

ZEB1 is involved in regulating HER2-positive breast cancer radiosensitivity by controlling EMT

MicroRNA-124 enhances response to radiotherapy in human epidermal growth factor receptor 2-positive breast cancer cells by targeting signal transducer and activator of transcription 3

Selection and Evaluation of Human Recombinant Antibodies against ErbB2 Antigen for Breast Cancer Immunotherapy

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