# Bacteriotherapy in Breast Cancer
## 4 Bacteria as a Carrier for Cancer Therapeutic Agents
### Lactobacillus plantarum  
_Lactobacillus plantarum_ is a gram-positive lactic acid bacterium and a member of the genus _Lactobacillus_, which is commonly present in many fermented food products [113]. It has preventive and antitumor effects via immunomodulatory mechanisms on multiple solid tumors, as well as breast cancer. The chemopre ability of _L. plantarum_ LS/07 (PRO), i.e., the prebiotic oligofructose-enriched inulin (PRE) and PRO-PRE combination were assessed in a rat model with breast cancer through oral administration. The results demonstrated that PRO, PRE, and PRO-PRE combination are significantly able to suppress the tumor frequency, raise the TCD4+ in tumor tissue, and decrease the serum level of TNF\(\alpha\). Furthermore, PRO and PRO-PRE can reduce the level of TCD8+ in blood and their increase in the tumor tissue [114]. CD8+ (cytotoxic) T cells can kill the tumor cells directly as well as breast tumor  
Figure 1: Activation of innate and adaptive immune response in the tumor microenvironment by _Salmonella_. Once _Salmonella_ colonizes tumor tissue, it induces an antitumor innate and adaptive immune response through several mechanisms as follows: (i) It promotes proinflammatory cytokines (IFN-\(\gamma\) and TNF-\(\alpha\)), while decreasing both anti-inflammatory (TGF-\(\beta\), IL-4) and angiogenic factors (VEGF) associated with tumor growth progression; (ii and iii) interactions between bacterial components (LPS and flagellin) and tumor cell receptors as TLR4 or TLR5, respectively, induce a cytokine secretion that promotes the recruitment of neutrophils, macrophages, T lymphocytes, B lymphocytes, and dendritic cells to the tumor microenvironment; (iv) _Salmonella_ colonization induces the expression of connexin 43 (Cx43), a molecule that plays a major role in the cross-presentation of tumor antigens by dendritic cells (DC) to CD8+ T-cells; (v) the presence of antitumor CD4+ T-cell induces the activation and differentiation of B lymphocytes in plasma cells, producing specific antitumor antibodies; (vi) Additionally, _Salmonella_ is able to suppress tumor growth inducing inflammasome, via activation of interleukin-1\(\beta\) (IL-1\(\beta\)) and TNF-\(\alpha\); (vii) examined an attenuated strain of _Salmonella_ engineered to express a truncated human interleukin-2 (IL2) protein called SalpIL2 (_Salmonella_ encoding IL-2 (SalpIL2). In murine models, a single oral dose of SalpIL2 reduced primary tumor volume and the number of metastatic lesions as a result of increased tumor-targeted NK-cell activity. The attenuated strain of _S. typhimurium_ labeled by green fluorescent protein (GFP) is also auxotrophic for leucine and arginine (termed _S. typhimurium_ A1). cells with higher levels of TCD8+ cells infiltration related to better survival rates among patients [115]. The T helper cells (Th cells), also known as CD4+ cells, show a heterogenous class of T-cells and help the response of TCD8+, particularly in the initial stages of tumor progression [116]. Different studies have demonstrated that _L. plantarum_ strains are able to inhibit the growth and proliferation through G0/G1 phase cell-cycle arrest in breast cancer cell lines including MCF-7, MDA-MB-231, and 4T1 [103; 117; 118; 119; 120]. _Lactobacillus casei_ CRL 431 is another member of genus _Lactobacillus_, which can suppress the growth of the tumor cells. The result of a study indicates that milk fermented by _L. casei_ can decrease or inhibit the tumor growth in a murine breast cancer model. The result showed the ability to modulate the immune response by reducing the infiltration of macrophages in the tumor and also increase the level of T CD8+ and TCD4+ [121]. Figure 2: Innate and adaptive immune responses to recombinant _Listeria_. (i) _L. monocytogenes_ (Lm) is internalized by antigen-presenting cells into phagosomes. During entry, Lm is sensed by Toll-like receptors leading to the activation of NF\(\kappa\)-B and synthesis of proinflammatory genes.