The ETS family of oncogenic transcription factors in solid tumours

ETS factor expression is aberrantly upregulated in solid tumours through chromosomal translocation and amplification.Activating mutations in KIT stabilize the ETV1 protein through the MEK–ERK pathway, thus driving an oncogenic transcriptional programme in gastrointestinal stromal tumours.Disruption of constitutive photomorphogenesis protein 1 (COP1)-mediated proteasomal degradation of ETS factors increases their protein stability and subsequent transcriptional activity in prostate and breast cancers.Mutations in the telomerase reverse transcriptase (TERT) promoter that generate an ETS-binding site are emerging as among the most frequent mutations in solid tumours.Gain of function cis-acting mutations in p53 (p53-GOF mutants) result in ETS2 protein–protein interactions and altered target gene expression affecting tumour growth, metastasis and chemotherapeutic resistance.ETS factors mediate lineage specification altering stem and progenitor populations in multiple cancer types.ETS fusion proteins interact with poly(ADP-ribose) polymerase 1 (PARP1) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs), both of which are mediators of DNA repair and genomic stability.ETS2 functions with p53-GOF mutants to epigenetically regulate super-enhancers.ETS factors function in both cell-autonomous and non-cell-autonomous manners in the tumour microenvironment to enhance cancer progression.Therapeutic strategies targeting ETS factor biology are emerging and should translate clinically in the next decade.