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. Author manuscript; available in PMC: 2021 Sep 1.
Published in final edited form as: Cancer Metastasis Rev. 2020 Sep;39(3):837–886. doi: 10.1007/s10555-020-09905-7

Figure 3: TGFβ stimulation of EMT, angiogenesis, and stemness in breast cancer progression toward metastasis.

Figure 3:

TGFβ binds TGFβ type I and II receptors and phosphorylates SMAD2 and SMAD3. SMADs 2/3 form a complex with SMAD4, translocate into the nucleus to bind HMGA2, a chromatin remodeling factor, and activate the transcription of SNAI1, SNAI2, ZEB1/2 and TWIST1. These transcription factors suppress CDH1 and increase VEGFA, in addition to regulating other genes in EMT (not shown). Canonical NOTCH signaling is initiated by interaction of ligands from one cell, e.g., Jagged (JAG1, JAG2), Delta-like (DLL1,2,3,4) and cognate NOTCH (NOTCH1,2,3,4,5) receptors on adjacent cells. The interaction activates cleavage of NOTCH receptor(s) by ADAM10 or ADAM17. γ-secretase cleavage releases NOTCH intracellular domain (NICD) that goes to the nucleus and interacts with RBPJ and MAML1 (Mastermind Like Transcriptional Coactivator 1) as a coactivator to stimulate gene transcription, including by interaction with NFκB. NICD also interacts with SMAD3 to regulate gene transcription. The indicated miRNAs and targets in this pathway are summarized in Tables 1–3.