The ZNF217 Oncogene and Metastatic Programs in Breast Cancer: 1. The Role of a Natural ZNF217 Variant in Mediating Bone Metastasis 2. Impact of Natural Molecules on Osteoblastogenesis and on ZNF217-driven Paclitaxel Resistance

Breast cancer remains a significant challenge due to its high metastatic potential, particularly to the bone, and its frequent resistance to chemotherapy. The oncoprotein ZNF217-WT is a key driver of both metastasis and chemotherapy resistance. This study aims to contribute to the understanding of ZNF217's isoforms role in breast cancer metastasis and to explore the therapeutic potential of natural compounds, particularly chrysin and its chemical derivatives. Identifying effective inhibitors from natural sources could offer a novel approach to overcoming chemotherapy resistance and managing bone metastases. In vitro experiments demonstrated that ZNF217-V enhances cancer cell proliferation, migration, and invasion more significantly than ZNF217-WT. In vivo models confirmed that ZNF217-V promotes the formation of micro-metastases in bone marrow, further establishing its role in bone-specific metastasis. Additionally, the natural flavonoid chrysin and its derivatives (CHRYS4 and CHRYS5) were evaluated as therapeutic agents to counter ZNF217-induced paclitaxel resistance and promote osteoblast differentiation in vitro. Chrysin enhanced osteoblast mineralization in vitro, suggesting it could help mitigate the osteolytic effects of bone metastasis. However, neither chrysin nor its derivatives overcame ZNF217-mediated paclitaxel resistance. This study contributes to understanding ZNF217’s isoforms role in breast cancer progression and highlights potential avenues for novel treatments targeting bone metastasis.