Dataset Information

CXCR4 Antagonist AMD3100 Reverses the Resistance to Tamoxifen in Breast Cancer via Inhibiting AKT Phosphorylation.

ABSTRACT: Endocrine therapy is a systemic therapy and has become the main treatment strategy for patients with estrogen receptor (ER)-positive breast cancer. However, tamoxifen resistance has become an insurmountable clinical challenge, and the underlying mechanisms are still poorly understood. In this study, we explored the roles of CXC chemokine receptor type 4 (CXCR4) in tamoxifen-treated breast cancer and tamoxifen resistance. Based on the Gene Expression Omnibus (GEO) database, high expression of CXCR4 was found to be associated with worse overall survival (hazard ratio [HR] = 4.646, p < 0.001) and cancer-specific survival (HR = 4.480, p < 0.001) in tamoxifen-treated breast cancer. CXCR4 was also positively correlated with the level of AKT phosphorylation and the resistance to tamoxifen in breast cancer. AMD3100 is a CXCR4 antagonist and was found to decrease phosphorylated (p)-AKT levels of tamoxifen-resistant cells. The reversal effect of AMD3100 on tamoxifen resistance was also confirmed in vitro and in vivo. Taken together, our study demonstrated that CXCR4 could be a potential prognostic biomarker for tamoxifen-treated breast cancer, and the combination of AMD3100 with tamoxifen could be a more efficacious therapeutic strategy for the treatment of tamoxifen resistance.

SUBMITTER: Zhou J

PROVIDER: S-EPMC7311345 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CXCR4 Antagonist AMD3100 Reverses the Resistance to Tamoxifen in Breast Cancer via Inhibiting AKT Phosphorylation.

Zhou Jun J Le Kehao K Xu Ming M Ming Jie J Yang Wen W Zhang Qiulei Q Lu Linlin L Xi Zihan Z Ruan Shengnan S Huang Tao T

Molecular therapy oncolytics 20200624

Endocrine therapy is a systemic therapy and has become the main treatment strategy for patients with estrogen receptor (ER)-positive breast cancer. However, tamoxifen resistance has become an insurmountable clinical challenge, and the underlying mechanisms are still poorly understood. In this study, we explored the roles of CXC chemokine receptor type 4 (CXCR4) in tamoxifen-treated breast cancer and tamoxifen resistance. Based on the Gene Expression Omnibus (GEO) database, high expression of CXC ...[more]

PMID: 32691010

Similar Datasets

Project description:BackgroundTamoxifen is a frontline therapy for estrogen receptor (ER)-positive breast cancer in premenopausal women. However, many patients develop resistance to tamoxifen, and the mechanism underlying tamoxifen resistance is not well understood. Here we examined whether ER-c-Src-HER2 complex formation is involved in tamoxifen resistance.MethodsMTT and colony formation assays were used to measure cell viability and proliferation. Western blot was used to detect protein expression and protein complex formations were detected by immunoprecipitation and immunofluorescence. SiRNA was used to examine the function of HER2 in of BT474 cells. An in vivo xenograft animal model was established to examine the role of c-Cbl in tumor growth.ResultsMTT and colony formation assay showed that BT474 cells are resistant to tamoxifen and T47D cells are sensitive to tamoxifen. Immunoprecipitation experiments revealed ER-c-Src-HER2 complex formation in BT474 cells but not in T47D cells. However, ER-c-Src-HER2 complex formation was detected after overexpressing HER2 in T47D cells and these cells were more resistant to tamoxifen. HER2 knockdown by siRNA in BT474 cells reduced ER-c-Src-HER2 complex formation and reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was also disrupted and tamoxifen resistance was reversed in BT474 cells by the c-Src inhibitor PP2 and HER2 antibody trastuzumab. Nystatin, a lipid raft inhibitor, reduced ER-c-Src-HER2 complex formation and partially reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was disrupted by overexpression of c-Cbl but not by the c-Cbl ubiquitin ligase mutant. In addition, c-Cbl could reverse tamoxifen resistance in BT474 cells, but the ubiquitin ligase mutant had no effect. The effect of c-Cbl was validated in BT474 tumor-bearing nude mice in vivo. Immunofluorescence also revealed ER-c-Src-HER2 complex formation was reduced in tumor tissues of nude mice with c-Cbl overexpression.ConclusionsOur results suggested that c-Cbl can reverse tamoxifen resistance in HER2-overexpressing breast cancer cells by inhibiting the formation of the ER-c-Src-HER2 complex.

Dataset Information

CXCR4 Antagonist AMD3100 Reverses the Resistance to Tamoxifen in Breast Cancer via Inhibiting AKT Phosphorylation.

Publications

CXCR4 Antagonist AMD3100 Reverses the Resistance to Tamoxifen in Breast Cancer via Inhibiting AKT Phosphorylation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets