This review explores how epithelial-mesenchymal transition (EMT), an important process of cancer progression and metastasis, is regulated by a group of transcription factors.
Some of the worst types of breast cancers present high levels of ZEB1/2, a family of transcription factors that are associated with EMT. In cells with high levels of ZEB1/2, ERK pathways are always active due to growth factors such as FGF. These pathways activate other transcription factors, such as ETS1/2, also enhancing ZEB1/2 expression as well as other genes associated with cancer phenotypes.
High levels of ZEB1/2 in aggressive carcinoma suppress the epithelial-splicing regulatory proteins ESRP1/2, which regulate isoforms of FGF receptors. By shifting from isoform IIIb to IIIc, they are capable of recognizing more FGF and trigger more positive feedback signaling to keep ZEB1/2 levels high. At the early stages, in response to TGF-beta, ZEB1/2 is upregulated by several transcription factors and then kept high later by positive feedback loops.
SNAIL, SLUG, and SMUC are also transcription factors that are not necessarily linked to mesenchymal phenotypes, but aberrant expression of these factors is actually correlated with some types of cancer and malignancies. Their regulation is directed through TGF-beta signaling in cooperation with active RAS pathways, which together induce rapid proliferation. There are other transcription factors that regulate their activity, but they are not necessary for their expression as TGF-beta alone can induce it. SLUG seems to be a substitute for SNAIL, while the functions of SMUC have not yet beed discovered.
TWIST1/2 are key regulators of EMT and metastasis. They are mediated by vimentin upregulation, which is a component of the cytoskeleton that confers carcinoma cells the ability to move around and invade tissue. The molecular mechanisms by which TWIST1/2 operate have yet to be understood. They are known to respond to TGF-beta as well as the inflammatory cytokine TNF-alpha.
In summary, the transcription of EMT transcription factors is enhanced by TGF-beta signaling during the early stages of carcinoma. As cancer progresses, the ERK and pathway becomes persistently activated by various growth factors and cytokines from cancer cells, sometimes in collaboration with TGF-β, further promoting EMT and aggressive cancer phenotypes. Notably, although these pathways are consistently activated in aggressive carcinoma cells, not all EMT-TFs are expressed simultaneously at high levels.
Citations:
Saitoh M. “Transcriptional regulation of EMT transcription factors in cancer”. Semin Cancer Biol. 2023 Dec; 97:21-29.
https://pubmed.ncbi.nlm.nih.gov/37802266/