Investigating the<i> </i>Microbiome in Breast Inflammatory and Cancerous Conditions: The Role of<i> Fusobacterium nucleatum</i> as Onco-Immune Modulator

Unlike other microbiomes, the breast microbiome remains stable across various factors, including pregnancy history, age and ethnicity. The breast is not a sterile organ, and its microbiota exhibits a distinct composition compared to other body sites. The breast microbiome is a community characterized by an abundance of Proteobacteria and Firmicutes, which represent the result of host microbial adaptation to the fatty acid environment in the tissue. The human milk microbiota (HMM) is a complex biological fluid enriched with immunomodulatory components and plays a pivotal role in shaping the neonatal gut ecosystem. Dysbiosis is strongly associated with mastitis. Risk factors for BC include genetic mutations, late menopause, obesity, estrogen metabolism and alterations in gut microbial diversity. Gut microbiota can increase estrogen bioavailability by deconjugating estrogen-glucuronide moieties in a process called estrobolome. Perturbations of this process increases circulating estrogens and risk of BC. Fusobacterium nucleatum has recently been associated with BC. It moves from the oral cavity to other body sites hematogenously. This review deals with the characteristics of the breast microbiome, with a focus on F. nucleatum, highlighting its dual role in promoting tumor growth and modulating immune responses. F. nucleatum acts both on the Wnt/β-catenin pathway by positively regulating MYC expression, and on apoptosis by inhibiting caspase 8. Furthermore, F. nucleatum binds to TIGIT and CEACAM1, inhibiting T cell cytotoxic activity and protecting tumor cells from immune cell attack. F. nucleatum also inhibits T cell function through the recruitment of myeloid suppressor cells (MDSCs). These cells express PD-L1, which further reduces T cell activation. A deeper understanding of F. nucleatum biology and its interactions with host cells and co-existing symbiotic microbiota could aid in the development of personalized anticancer therapy.