Histone lysine demethylases in breast cancer: molecular mechanisms, biological functions, and therapeutic intervention

Breast cancer is a highly heterogeneous disease characterized by diverse molecular subtypes and complex pathogenesis. Recent advances in epigenetics have unveiled the crucial roles of lysine demethylases (KDMs) in modulating gene expression and chromatin dynamics, thereby influencing breast cancer progression, including metastasis, and therapeutic resistance. KDMs, which remove methyl groups from histone lysine residues, are mainly categorized into seven subfamilies (KDM1-7) based on their catalytic mechanisms and substrate specificities. Meanwhile, each subfamily exhibits distinct roles in breast cancer, ranging from transcriptional regulation and chromatin remodeling to interactions with non-histone proteins. Notably, KDMs exhibit subtype-specific functions in breast cancer. KDMs are also implicated in various hallmarks of breast cancer, including DNA damage response, cell cycle regulation, stemness maintenance, metabolic reprogramming, and modulation of the tumor microenvironment. KDMs represent promising targets for overcoming therapeutic resistance in breast cancer. Inhibitors targeting KDMs have shown potential to enhance the efficacy of endocrine therapy, chemotherapy, and targeted therapy by modulating oncogenic signaling pathways. The KDM family members are intricately involved in the molecular pathogenesis of breast cancer, offering a rich landscape for therapeutic intervention. This review summarizes the multifaceted molecular mechanisms and biological functions of KDMs in breast cancer, highlighting their potential as therapeutic targets.