Nuclear isoform of RAPH1 interacts with FOXQ1 to promote progression and radioresistance in triple-negative breast cancer through the STAT3 pathway

Radioresistance limits the efficacy of radiotherapy against triple-negative breast cancer (TNBC). Epithelial-to-mesenchymal transition (EMT) is closely related to tumor radioresistance. In this work, we attempted to identify the key EMT-related transcription factor(s) that can induce radioresistance in TNBC cells. A set of 44 EMT transcription factors were analyzed in parental and radioresistant TNBC cell lines. The function of FOXQ1, a differentially expressed transcription factor, was determined in TNBC radioresistance. FOXQ1-interacting proteins were identified by co-immunoprecipitation and mass spectrometry. Compared with parental cells, FOXQ1 was significantly upregulated in radioresistant TNBC cells. Silencing of FOXQ1 increased the radiosensitiviy of radioresistant TNBC cells both in vitro and in vivo. FOXQ1 associated with a nuclear isoform of RAPH1 (named RAPH1-i3) in radioresistant TNBC cells. Overexpression of RAPH1-i3 enhanced TNBC cell proliferation and migration, and most interestingly, induced radioresistance in parental TNBC cells when co-expressed with FOXQ1. Mechanistically, co-expression of RAPH1-i3 and FOXQ1 activated the STAT3 signaling pathway and increased the expression of CCND1, MCL1, Bcl-XL, MMP2, and MMP9. Depletion of RAPH1-i3 impaired the radioresistance of radioresistant TNBC cells. Additionally, RAPH1-i3 upregulation was associated with advanced tumor stage and reduced disease-free survival in TNBC patients. These results collectively show that RAPH1-i3 interacts with FOXQ1 to promote TNBC progression and radioresistance via activation of STAT3 signaling. RAPH1-i3 and FOXQ1 may represent therapeutic targets for overcoming the radioresistance of TNBC.