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Increasing studies have indicated that circular RNAs (circRNAs) play pivotal roles in various cancers. Here, we aimed to explore the roles of circRNAs in breast cancer. We identified a novel circRNA circKDM4B (hsa_circ_0002926) by whole-transcriptome sequencing and validated this by Real-time quantitative polymerase chain reaction (RT-qPCR) and Sanger sequencing. It was significantly decreased in breast cancer tissues compared with adjacent non-tumor tissues. Furthermore, circKDM4B, which is mainly localized in the cytoplasm, was more resistant to actinomycin D or ribonuclease R than its linear transcript KDM4B. In addition, the overexpression of circKDM4B inhibited cell migration and invasion in vitro, while knockdown of circKDM4B induced the opposite effects. In vivo, circKDM4B suppressed tumor growth and metastasis. Additionally, circKDM4B inhibited migration and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro and angiogenesis in vivo. Mechanically, circKDM4B sponged miR-675 to upregulate the expression of NEDD4-like E3 ubiquitin protein ligase (NEDD4L), which catalyzes ubiquitination of PI3KCA, thereby inhibiting PI3K/AKT and VEGFA secretion. Collectively, these findings uncovered the tumor-suppressor role of circKDM4B in breast cancer, especially in angiogenesis and tumor metastasis, indicating that circKDM4B could be a potential therapeutic target for breast cancer progression.

Background Accumulating evidence indicates that the crosstalk between tumor cells and the microenvironment influences human cancer progression. However, the expression pattern, function role in the crosstalk between tumor cells and tumor microenvironment, and underlying mechanism of lncRNAs-related tumorigenesis in breast cancer are unknown. Methods The expression lncRNA-THAP7-AS1 in breast cancer (BC) were identified by in BC tissues. The functional roles of THAP7-AS1 were confirmed by in vitro and in vivo experiments. RNA-pulldown followed by mass spectrometry, RNA Immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) assays and luciferase reporter assay revealed the mechanisms of THAP7-AS1 in BC. RT-qPCR, ELISA assays, Flow cytometry, ChIP assays and luciferase reporter assay elucidated the crosstalk between tumor cells and (tumor-associated macrophages) TAMs. Results Here, we demonstrate that long non-coding RNA (lncRNA) THAP7-AS1 induces polarization of macrophages to the M2 phenotype in an IL-4-dependent manner, and M2 tumor-associated macrophages (TAMs) secreted IL-10, which then facilitates the progression of breast cancer (BC). Mechanistically, THAP7-AS1 promoted the combination between SNF2H, SNF2L, and BAF155 and recruited the SWI/SNF complex to the promoter of EGFR to upregulate its expression, and then induced IL-4-mediated M2 polarization of macrophages via activation of the EGFR-ELK1 signaling. Reciprocally, IL-10 released from M2 TAMs upregulates CEBP-β-dependent P300 expression, and then P300, synergistically worked with c-MYC and upregulated THAP7-AS1 expression in BC cells, which constituting a feed-forward loop between tumor cells and TAMs. Moreover, THAP7-AS1 knockdown inhibits the invasion, metastasis and M2 macrophage polarization of breast cancer in vivo. Conclusions Our study highlights the role of THAP7-AS1 in the regulation crosstalk between TAM and tumor cells in BC progression and may provide a novel therapeutic target for BC treatment.