Oncoprotein SET dynamically regulates cellular stress response through nucleocytoplasmic transport in breast cancer

SETβ is the predominant isoform of oncoprotein SE translocation (SET) in various breast cancer cell lines. Interactome-transcriptome analysis has shown that SETβ is intimately associated with cellular stress response. Among various exogenous stimuli, formaldehyde (FA) causes distinct biological effects in a dose-dependent manner. In response to FA at different concentrations, SET dynamically shuttles between the nucleus and cytoplasm, performing diverse biofunctions to restore homeostasis. At a low concentration, FA acts as an epidermal growth factor (EGF) and activates the HER2 receptor and downstream signaling pathways in HER2⁺ breast cancer cells, resulting in enhanced cell proliferation. Nucleocytoplasmic transport of SETβ is controlled by the PI3K/PKCα/CK2α axis and depletion or blockade of the transport of SETβ suppresses EGF-induced activation of AKT and ERK. SETβ also inhibits not only stress-induced activation of p38 MAPK signaling pathway, but also assembly of stress granules by hindering formation of the G3BP1-RNA complex. Our findings suggest that SET functions as an important regulator which modulates cellular stress signaling pathways dynamically.