The Molecular Mechanism Of G3BP1 In Tamoxifen Resistance In Breast Cancer

Background and purpose: Breast cancer is the most common malignancy worldwide,and tamoxifen is the most commonly used endocrine therapy drug in patients with estrogen receptor(ER)-positive breast cancer,but treatment resistance remains a major clinical challenge.G3BP1 is a Ras GAP-SH3 domain-specific binding protein,which is closely related to the occurrence and development of a variety of malignant tumors.Previous studies in our group also confirmed that G3BP1 is closely related to breast cancer endocrine therapy.This study aims to investigate the mechanisms associated with G3BP1 and tamoxifen resistance in breast cancer.Method: 1.Construction of the tamoxifen-resistant cells MCF-7Tam R based on ER+ /HER2-breast cancer cells MCF-7.2.Detection of G3BP1 protein expression levels in MCF-7Tam R;G3BP1 expression levels were downregulated by lentiviral transfection to construct the G3BP1 lowexpression cell line sh G3BP1-MCF-7Tam R.3.The sensitivity to tamoxifen,the abilities of migration and invasion of MCF-7Tam R,sh G3BP1-MCF-7Tam R was observed by CCK-8 and Transwell assay.4.The effect of G3BP1 protein on PI3K/AKT/m TOR signaling pathway were detected by Western blot.5.A total of 40 surgical tumor wax samples from breast cancer patients who had previously received tamoxifen adjuvant therapy were collected,divided into tamoxifen treatment resistant group and sensitive group according to the time of disease recurrence,and immunohistochemical staining was performed to analyze the expression of G3BP1 protein in the tumor tissues of the two groups.According to the immunohistochemical staining,it was divided into G3BP1 protein high expression group and ground expression group,and its relationship with disease-free survival rate(DFS)was analyzed.Results: 1.The expression of G3BP1 protein in MCF-7Tam R was significantly increased(P<0.01),and after G3BP1 knockout,its sensitivity to tamoxifen was significantly restored(P<0.01),and its migration and invasion ability were decreased(P<0.05).2.Compared with MCF-7,the expression levels of p‐PI3K,p‐AKT,and m TOR proteins in MCF-7Tam R were significantly increased,while total PI3 K and AKT proteins did not change significantly.After downregulating the expression of G3BP1 protein,the expression levels of p‐PI3K,p‐AKT,and m TOR proteins were significantly downregulated,and there was no significant change in the expression of total PI3 K and AKT proteins.3.In the tumor tissues of patients receiving tamoxifen adjuvant therapy,the expression of G3BP1 protein in the drug-resistant group was significantly higher than that in the sensitive group(P<0.05),and the DFS in the G3BP1 protein high expression group was smaller than that in the low expression group(P<0.05).Conclusions: G3BP1 is associated with tamoxifen treatment resistance in breast cancer,and the PI3K/AKT/m TOR signaling pathway may be one of mechanisms.