Yuhan Bai, Xiangyi Kong, J. Wang
Breast cancer remains a leading cause of morbidity and mortality among women worldwide, with significant heterogeneity in its development and treatment response. Recent advances in understanding the roles of the microbiome and epigenetic regulation have opened new avenues for addressing the complexities of breast cancer progression and therapeutic resistance. This review explores the intricate relationship between the gut and intratumoral microbiomes and epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNAs. Specifically, we examine how microbial metabolites, particularly short-chain fatty acids (SCFAs), regulate gene expression via epigenetic mechanisms, influencing tumor growth, metastasis, and treatment response. The impact of metabolic diseases, including obesity and type 2 diabetes mellitus (T2DM), on breast cancer risk through microbiome-mediated epigenetic changes is also discussed. Furthermore, the review highlights emerging therapeutic strategies that integrate microbiome modulation with epigenetic therapies, including the use of probiotics, dietary interventions, and fecal microbiota transplantation (FMT), as well as DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors. These innovative approaches hold promise for overcoming treatment resistance and improving clinical outcomes in breast cancer patients. Future research should focus on elucidating the molecular pathways through which the microbiome influences epigenetic regulation and developing personalized, microbiome-targeted therapies that enhance the efficacy of existing treatments. By targeting both the genetic and epigenetic drivers of breast cancer, microbiome-based interventions represent a novel frontier in the fight against this challenging disease.