Abstract
Breast cancer remains one of the most prevalent and deadly malignancies among women worldwide. The F-box protein family, a core component of the SCF (SKP1-Cullin1-F-box) E3 ubiquitin ligase complex, plays a pivotal role in determining substrate specificity for ubiquitin-mediated proteasomal degradation. Beyond their classical functions in cell cycle regulation and signaling pathways, F-box proteins are increasingly recognized for their involvement in key oncogenic processes, including breast cancer stem cell (BCSC) maintenance, metastasis, and therapy resistance. Based on differences in their C-terminal domains, F-box proteins are classified into three subfamilies: FBXL, FBXW, and FBXO. Certain members, such as SKP2 and FBXL10, act as oncogenes, whereas others, like FBXW7 and FBXO15, function as tumor suppressors. Notably, some proteins - including FBXO11 and FBXO22 - exhibit dual or context-dependent roles that vary by tissue type or disease stage. With their diverse and critical functions, F-box proteins have emerged as promising therapeutic targets in breast cancer. Current strategies under investigation include small-molecule inhibitors (SMIs) and RNA interference (RNAi). This review highlights recent advances in understanding the molecular mechanisms of F-box proteins in breast cancer and explores their potential in targeted therapy.