Table 2.

Microbial contributions to oncogenesis and tumor growth.

Effects	Mechanisms
Genome damage	Some pathobionts, such as E. coli and S. epidermidis cultured from breast tissue has been shown to induce DNA double-strand breaks in HeLa cells in vitro (122).
Pro-inflammatory response	Dysbiosis of the BM disrupts the local homeostatic levels of MAMPs and increases the levels of ROS. This triggers the expression of pro-inflammatory cytokines and the release of DAMPs, which drives a positive feedback loop towards a chronic pathogenic inflammatory response, promoting tumorigenesis or enhancing pre-existing tumor growth (167).
Modulate immune response and survival	1) TLR signaling: In all types of BC, TLR (microbial sensing) receptors are significantly altered. BC features upregulated TLR4 receptors, which stimulate pro-inflammatory, pro-survival pathways (e.g., NF-κB) (146, 168, 169). In this regard, bacterial MAMPs bind to and modulate TLR4. For example, LPS binds to TLR4+ monocytes and promote their differentiation to pro-tumorigenic M2 macrophages (170, 171). 2) Immune cell recruitment: In healthy breast tissue, the abundance of certain bacterial strains, such as Streptococcus, Propionibacterium, Staphylococcus, and Acinetobacter positively correlate with that of tumor-targeting cytotoxic T-cell (e.g. CD8+), while their depletion contributes to an immunosuppressive TME typically found in BC (146). Conversely, the abundance of pathobionts, such as F. nucleatum inhibits the infiltration and effects of tumor-infiltrating lymphocytes (172) 3) Oncogene expression: Certain bacterial signatures can potentially regulate oncogene expression. For example, the presence of Staphylococcus has been negatively correlated with tumor necrosis factor receptor-associated factor 4 (TRAF4) (146, 173).
Promote Metastasis	1) Intracellular Pathobiont influence gene expression: Certain pathobionts, such as Fusobacterium nucleatum invade cancer cells and induce their proliferation while effectively evading the immune system (174). In BC, F. nucleatum colonization accelerates tumor growth and metastasis (172). Similarly, the presence of Haemophilus influenzae, has been correlated with the expression of pro-tumorigenic pathways (142). 2) MAMPs: Increased levels of circulating MAMPs, such as LPS has been associated with BC metastasis by inducing a monocyte-mediated endothelial adhesion of circulating cancer cells (175) or by inducing the production of pro-metastatic neutrophil extracellular traps (NETs) (176). Lymphovascular invasion is associated with a reduced abundance of Oblitimonas in the TM (146).