<p>Breast cancer represents a multifaceted and heterogeneous condition characterized by both genetic and epigenetic alterations. Among these, epigenetic modifications—such as DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs—play pivotal roles in tumor initiation, progression, therapeutic resistance, and immune evasion. These alterations contribute to dysregulation of estrogen signalling, endocrine therapy resistance, and metabolic rewiring, posing challenges for conventional treatment strategies. Notably, our previous findings reveal that 27-hydroxycholesterol, an endogenous selective estrogen modulator, can induce epigenetic changes in (ER)-positive breast cancer cells. This review provides a comprehensive overview of the landscape of epigenetic dysregulation in breast cancer, emphasizing its impact on disease progression and therapeutic resistance. It details the intricate interplay&#xa0;between epigenetic players and the tumor immune microenvironment, which plays a crucial role in shaping treatment responses. In addition, the review highlights the on-going clinical trials and suggests addressing the gaps present in dissecting pathways of epigenetic reprogramming in breast cancer evolution and therapy outcomes. Unraveling these mechanisms reinstates opportunities for potential therapies targeting epigenetic pathways along with the conventional medicine, which is required in transformation of clinical management of breast cancer and potential enhancement of the patient’s lifespan.</p>