Fig. 7.

TNFR2 supports BCSC growth and development. Once TNFR2 is activated via Mb-TNF-α or R2TNF, multiple proteins including EGFR, VEGFR2, IL-6/JAK, HER2, and NF-κB are activated. EGFR activation leads to ERK1/2 phosphorylation, inducing MNK, xIAP, and Snai 2. VEGFR2 activation triggers PI3K/Akt activation, stimulating mTORC, which along with IL-6/JAK, HER2, and NF-κB, promotes STAT3 activation. STAT3 induces various oncogenic proteins, including Cycline D1, MYC, surviving, VEGF, MMPs, Bcl-XL, IL-6, IL-10, and TGF-β. IKKα and IKKβ activation promote HIF-1α, OCT4, CCDC88A, and Akt stimulation and the release of NF-κB-p52 to the nucleus and up-regulate TAZ-enhancing CYR61 production. HIF-1α will trigger CD47 and SLUG/Jagged1 or SLUG/CD44, while Akt stimulates the RAS/RAF/MEK/ERK pathway. These proteins lead to Notch, Hedgehog, Wnt, Hippo, SMAD, and PPAR stimulation, promoting BCSC self-renewal, EMT development, angiogenesis, and survival. TNFR2, tumor necrosis receptor type 2; Mb-TNF-α, membrane-bound tumor necrosis factor; TRAF, TNF receptor associated factor; T2bs-C, TRAF2-binding site C; T2bs-N, TRAF2-binding site N; Akt, protein kinase B/serine-threonine kinase; mTOR, mammalian (or mechanistic) target of rapamycin; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2; EMT, epithelial-mesenchymal; MMPs, matrix metalloproteinases; c-MYC, cellular myelocytomatosis; STAT, signal transducer and activator of transcriptions; IL-6, interleukin 6; IL-10, interleukin 10; TGF-β, transforming-growth factor β; HIF-1α, hypoxia inducible factor 1 alpha; IKKs, IκB kinases; Bcl-2, B cell lymphoma 2; HER2, human epidermal growth factor receptor 2; PI3K, phosphoinositide 3-kinases; ERK, extracellular signal-regulated kinase; MNK, MAPK interacting kinase; PPAR, peroxisome proliferator-activated receptor