Abstract
BACKGROUND: The tumor necrosis factor-α-induced protein 8-like 3 (TNFAIP8L3, TIPE3) plays a critical role in phosphoinositide transport and metabolism to facilitate PI3K-AKT signaling activation. Elevated TIPE3 expression has been observed in multiple malignancies, including esophageal, cervical, colon, and lung cancers, suggesting its potential oncogenic role in tumor progression. However, the precise molecular mechanisms by which TIPE3 regulates breast cancer progression remain largely unclear. This study aims to investigate the role of TIPE3 in breast cancer cell growth and metastasis. METHODS: TIPE3 expression in 100 paired breast cancer and adjacent tissues was analyzed via immunohistochemistry. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assessed TIPE3 levels in breast cancer cell lines (MCF7, SKBR3, MDA-MB-231, MDA-MB-468) and normal mammary epithelial cell (MCF10A). TIPE3 overexpression and TIPE3 knockdown lentiviral constructs were generated and transfected into MCF7 and MDA-MB-231 cells. Functional assays, including Cell Counting Kit-8 (CCK-8), colony formation, cell cycle analysis, wound healing, and transwell invasion assays, evaluated proliferation, migration, and invasion. Tumor growth and metastasis were assessed in BALB/c nude mice. Western blot, qRT-PCR, and IHC examined the impact of TIPE3 on AKT-GSK3β-β-catenin/Snail signaling and epithelial-mesenchymal transition (EMT) marker expression. RESULTS: TIPE3 expression was significantly upregulated in breast cancer tissues and cell lines. Stable TIPE3 overexpression (MCF7-TIPE3) and TIPE3 knockdown (MDA-MB-231-shTIPE3) cell lines were established. TIPE3 overexpression promoted proliferation, G1/S transition, migration, and invasion, whereas TIPE3 knockdown inhibited these processes and suppressed tumor growth and lung metastasis in nude mice. TIPE3 regulated the AKT-GSK3β-β-catenin/Snail signaling pathway, enhancing EMT marker expression while downregulating E-cadherin. CONCLUSIONS: TIPE3 expression is elevated in breast cancer and likely promotes breast cancer growth and metastasis through the AKT-GSK3β-β-catenin/Snail pathway. TIPE3 may be a novel therapeutic target for breast cancer.