# Extracellular Vesicles and Artificial Intelligence: Unique Weapons against Breast Cancer
## 2 EVs in Breast Cancer
### EVs' Involvement in BC Drug Resistance  
Therapeutic approaches in BC treatment are strongly related to the tumor classification, which provides information about the intrinsic future of drug resistance. The positive hormone receptors (HRs) in BC, such as the estrogen receptor (ER+) and the progesterone receptor (PR+), are generally sensitive to selective estrogen receptor modulators (SERMs), such as tamoxifen, and selective estrogen receptor downregulators (SERDs), such as full-vestrant [68]. Trastuzumab and lapatinib were found to be efficient in human epidermal growth factor receptor 2 (HER2)-positive BC treatment [69; 70]. For both HR+ and HER2+BC, chemotherapy and radiotherapy are suggested as neoadjuvant/adjuvant treatments to support a surgical approach. The cyclin-dependent kinase 4/6 inhibitor is now used in HR+/HER2-BC treatment and was recently proposed for TNBC treatment [71]. TNBCs cause low/absent expression levels of all HRs and present poor sensitivity to treatment, earning a reputation as a very aggressive and difficult-to-treat type of tumor. Regarding the intrinsic resistance phenomena, due to tumor heterogeneity, genetic and epigenetic mutations/futures, and the absence of expression of the drug target, acquired resistance is accompanied by a progressive loss of sensitivity to treatment over time, possibly due to alternative pathway expression or mutations that prevent drug efficiency. Alterations could occur in both cancer cells and/or at the expense of the tumor microenvironment (TME) [72]. The immunosuppressive microenvironment that can occur due to the presence of tumor-associated neutrophils (TANs), regulatory T cells (Tregs), and tumor-associated macrophages (TAMs), such as the secretion of immune suppression molecules, for instance, programmed cell death ligand 1 (PD-L1), leads to the acquisition of a treatment-resistant phenotype in BC. EVs are involved in therapy resistance; through their cargo, they influence the TME, although in a loop, TME cells communicate with BC cells via EVs. First, BC-derived EVs containing upregulated miR-146a are able to induce the transition of fibroblasts into cancer-associated fibroblasts (CAFs), a fundamental event in the formation of the TME [73]. CAFs promote more aggressive disease via several mechanisms, such as CAF-derived EVs enriched in miR-92 that induce increased PD-L1 expression in BC, inhibiting T cell performance with a consequent resistance to immunotherapies through immune suppression mechanisms [74]. MSCs are able to differentiate into adipocytes, chondrocytes, and osteoblasts, exhibiting plastic adherence, and they can be defined according to the presence/absence of the following biomarkers: CD73+, CD90+, CD105+ cells, CD14\(-\), CD34\(-\), CD45\(-\), and human leukocyte antigen-DR isotype (HLA-DR) [75]. In physiological conditions, MSCs act as immunomodulators, but in BC-promoting tumor progression [76], EVs collected from MSCs promote increases in migration and proliferation in ER + BC via the wnt/\(\beta\)-catenin pathway, which is recognized to be implicated in BC drug resistance [77]. The controversial tumor-suppressor role of EV-derived MSCs in BC requires further research because they are reportedly able to suppress angiogenesis via the downregulation of VEGF, partially through miR-16 [60], and through the modulation of mTOR/HIF-1 alpha/VEGF signaling suppression through miR-100 [78]. The involvement of RNA/proteins in EV cargo in the polarization of M2-type anti-inflammatory/immunosuppressive macrophages (alternatively activated) is well characterized and connected to cancer progression, lymph node metastasis, and responses to chemotherapy. An M2 immunosuppressive phenotype can be induced via an EV-mediated interplay between macrophages, cancer cells, and TME cells, which is associated with a poor prognostic outcome and lymph node metastasis [79; 80; 81; 82; 83; 84]. Both M1-type pro-inflammatory (classically activated) and M2 macrophages were identified in the TME.