The E2F1/SBK1 axis activates the Notch signaling pathway to accelerate the malignant progression of breast cancer.

Breast cancer is one of the leading causes of cancer mortality in women, and its incidence continues to increase worldwide. It has been confirmed that E2F transcription factor 1 (E2F1) is associated with increased malignancy and poor prognosis in breast cancer tumors. Although SH3 domain-binding kinase 1 (SBK1) expression is upregulated in various cancers, its function in breast cancer has not been fully investigated. Therefore, it is of great significance to explore whether E2F1 and SBK1 cooperate to regulate the progression of breast cancer. UALCAN and GEPIA websites were used to predict the expression of SBK1 in different tumors, especially breast cancer tumors. Real-time quantitative PCR (RT-qPCR) and Western blotting (WB) assays were employed to quantify the levels of mRNA and proteins, respectively. Cell proliferation, apoptosis, migration, and invasion were conducted using 5-ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry, and Transwell assay. Commercial kits were applied to measure the lactate and glucose levels. We constructed a mouse xenograft model to verify the effect of SBK1 on breast cancer in vivo. Interrelation between E2F1 and SBK1 was identified by Chromatin Immunoprecipitation (ChIP) and dual-luciferase labeling assay. Through bioinformatics analysis, WB, and RT-qPCR experiments, it was observed that both SBK1 and E2F1 were significantly overexpressed in breast cancer tissues and cells. Silencing SBK1 inhibited the malignant proliferation, migration, invasion, glycolysis, and the macrophage M2 polarization, but promoted apoptosis of breast cancer cells. Specifically, silencing SBK1 inhibited the growth of subcutaneously transplanted tumors in mice. Additionally, E2F1 was confirmed to positively regulate SBK1, and the anticancer effect of E2F1 knockdown was rescued by SBK1 overexpression. Meanwhile, the expression of the Notch signaling pathway-related proteins was downregulated after E2F1 knockdown and could also be restored by SBK1 overexpression. This study elucidated the mechanism of SBK1/E2F1 involved in the progression of breast cancer and provided a new target for the treatment of breast cancer.