Abstract
Objective: ER+ breast cancer is the most common type of breast cancer, which seriously affects the physical and mental health of women. Recently, lncRNAs mediated tumor-associated macrophages (TAM) were identified to involve in tumorigenesis. Therefore, the present study aimed at demonstrating the regulatory network of GNAS-AS1 in TAM-mediated ER+ breast cancer progress.Methods: The expression levels of genes were evaluated using qRT-PCR. The proportions of polarized macrophages (M1, M2) were assessed by flow cytometry. Cell proliferation, migration and invasion were evaluated by CCK-8, wound healing and transwell assay, respectively. Double-luciferase reporter system was used to detect the interaction between molecules. Western blot was applied to test protein levels.Results: The expression of GNAS-AS1 was obviously increased in ER+ breast cancer tissues and cell lines, as well as M2 macrophages. GNAS-AS1 facilitated the capabilities of proliferation, migration and invasion of ER+ breast cancer cells by accelerating M2 macrophage polarization via directly sponging miR-433-3p. GATA3, as a target of miR-433-3p, could positively regulate by GNAS-AS1. Furthermore, either miR-433-3p overexpression or GATA3 knockdown impaired the effects of GNAS-AS1 on M2 macrophage polarization and ER+ breast cancer cells progression.Conclusion: GNAS-AS1/miR-433-3p/GATA3 axis promoted proliferation, metastasis of ER+ breast cancer cells by accelerating M2 macrophage polarization. The mechanism may provide a new strategy and target for ER+ breast cancer treatment.
Highlights
Breast cancer, as a malignant tumor that seriously affects the survival and life of women, is known as the first killer of women [1]
Cancer tissues and adjacent non-caner tissues were obtained from ER+ breast cancer patients to investigate the expression of GNAS-AS1. real-time quantitative PCR (qRT-PCR) assay found that GNAS-AS1 was dramatically increased in cancer tissues (Figure 1A)
The macrophage markers were examined by qRT-PCR that showed that M1 macrophage markers (TNF-α and IL-6) were markedly increased after LPS+IFN-γ treatment, and M2 macrophage markers (IL-10 and Arginase-1) were dramatically elevated after IL-4 treatment (Figure 1D,E)
Summary
As a malignant tumor that seriously affects the survival and life of women, is known as the first killer of women [1]. Current evidences have suggested that the incidence and mortality rate of breast cancer are significant increase, with an estimated 278,800 new cases and 64,600 deaths in China, the dramatic advances in diagnosis and treatment [2]. ER+ breast cancer is the most common subtype of this disease, which accounts for nearly 75% of total [3]. The treatment options for ER+ breast cancer includes surgery, chemotherapy, radiation therapy, molecular targeted therapy, immunotherapy and so on [4]. Current clinical treatment has been challenged due to the therapeutic resistant of patients, which caused by the molecular heterogeneity and complicated biology process of ER+ breast cancer [5]. To explore the molecular mechanisms underlying ER+ breast cancer progression may provide great value for searching novel therapeutic strategies and potential targets of breast cancer
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