Figure 3.

Signaling pathways in TNBC targeted by multiple components of the MD oils. Signaling through the PI3K/Akt/mTOR pathway facilitates cell proliferation, invasion, and survival. Growth factor receptors (e.g., insulin receptor, human epidermal growth factor receptors) activate PI3K, which activates Akt and subsequently mTOR. Components from the MD shown to have inhibitory effects on this pathway include DHA from fish oil in addition to oleocanthal and oleanolic acid from olive oil. COX2 is involved in BC initiation, inflammation, invasion and metastasis. Under basal conditions NF-κB (p65 and p50) is sequestered in the cytosol by inhibitor of κB (IκB) proteins. Activation of inflammatory cytokine receptors (e.g., tumor necrosis factor (TNF) receptor) activates inhibitory κB kinase (IKK) complexes, which phosphorylate IκB proteins for degradation leading to stabilization and nuclear translocation of NF-κB. In the nucleus, NF-κB activates a myriad of target genes, such as Ptgs2, the gene encoding the COX2 protein. MD components that inhibit this signaling pathway include the fish oil ω-3 fatty acids in addition to oleuropein, oleanolic acid and oleocanthal from olive oil. Finally, the Wnt/β-catenin signaling pathway increases TNBC cell proliferation, migration and chemoresistance. Under normal conditions, β-catenin is sequestered and degraded in the cytosol by a destruction complex containing axin, adenomatous polyposis coli (APC), glycogen synthase kinase-3 (GSK3)β and casein kinase (CK1). Interaction of Wnt ligands with receptor complexes (e.g., low-density lipoprotein receptor-related protein (LRP)5/LRP6/frizzled) leads to dissociation of β-catenin from the destruction complex, which leads to its stabilization and nuclear accumulation. Both DHA from fish oil and hydroxytyrosol from olive oil have inhibitory effects on the Wnt/β-catenin pathway.