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

Abstract

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.

Assessment of the expression pattern of mTOR‐associated lncRNAs and their genomic variants in the patients with breast cancer

“…Moreover, we observed a trend toward higher expression of SNHG3 in HER2‐positive tumors compared with the HER2‐negative ones. This finding is in accordance with the results of a recent study, which demonstrated that expression of ZEB1, an upregulated gene by SNHG3 , has been shown to be positively correlated with HER2 expression (Han, Zhu, Xu, Shui, & Lu, ).…”

“…mTOR: mechanistic target of rapamycin; ROC: receiver operating characteristic; SNHG1: small nucleolar RNA host gene 1 [Color figure can be viewed at wileyonlinelibrary.com] expression of SNHG3 in HER2-positive tumors compared with the HER2negative ones. This finding is in accordance with the results of a recent study, which demonstrated that expression of ZEB1, an upregulated gene by SNHG3, has been shown to be positively correlated with HER2 expression(Han, Zhu, Xu, Shui, & Lu, 2018).…”

“…In accordance with this study, we detected higher levels of SNHG3 in TNBC compared with all other molecular subtypes. Moreover, we observed a trend toward higher (Han, Zhu, Xu, Shui, & Lu, 2018).…”