Abstract
Summary Triple-negative breast cancers (TNBCs) are characterized by high rates of recurrence and aggressiveness, and poor clinical outcomes. Deregulated E3 ligases are involved in breast cancer pathogenesis and progression, but the underlying mechanisms are unclear. Here, we found that F-box and leucine-rich repeat protein 16 (FBXL16) acts as a tumor suppressor in TNBC. Specifically, FBXL16 directly binds to HIF1α and induces its ubiquitination and degradation, regardless of the tumor microenvironment, resulting in blockade of the HIF1α-mediated epithelial-mesenchymal transition (EMT) and angiogenesis features of breast cancer. In TNBC, FBXL16 expression is downregulated by the p38/miR-135b-3p axis, and loss of FBXL16 expression restores HIF1α-mediated metastatic features of breast cancer. Low expression of FBXL16 is associated with high-grade and lymph node-positive tumors and poor overall survival of breast cancer. Together, these findings reveal a novel suppressive role of FBXL16 in regulating breast cancer progression and suggest that modulation of FBXL16 expression may offer a favorable strategy for treatment of patients with metastatic breast cancer, including TNBCs.
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