TRIB1 modulates transcriptional programming in breast cancer cells to regulate cell proliferation

Abstract

AbstractThe pseudokinase Tribbles Homolog 1 (TRIB1) is a known driver of tumorigenesis in acute myeloid leukemia and is encoded upstream of the oncogeneMYCat the 8q24 locus. We observed thatTRIB1/MYCco-amplification is associated with decreased relapse-free and overall survival in breast cancer patients, but the role ofTRIB1in this disease has not been well characterized.TRIB1knockdown in multiple breast cancer cell lines inhibited cell proliferation and suppressedMYCexpression, implicatingTRIB1in breast cancer cell proliferation. Transcriptomic and cell cycle analysis revealed cell cycle regulation as the likely mechanism through whichTRIB1influences breast cancer cell proliferation.TRIB1knockdown also resulted in significant changes in both estrogen receptor (ER) and β-catenin associated transcription. Interrogating the TRIB1 interactome in breast cancer cells by qPLEX-RIME reinforced the known association between TRIB1 and ubiquitination, while revealing a range of previously undescribed TRIB1 associated factors. Further analysis of the association between TRIB1, β-catenin and FERMT2 suggests TRIB1 may regulate β-catenin activity by controlling the levels of both β-catenin, and its co-factor FERMT2. Together, these results suggest that coregulation of β-catenin and ER-driven transcription by TRIB1, facilitates regulation ofMYCexpression and breast cancer cell proliferation.SignificanceThe pseudokinaseTRIB1is frequently co-amplified in breast cancers with the potent oncogeneMYC, although the functional consequences of this event are not well understood. This study demonstratesTRIB1is a regulator of cell cycle progression andMYCexpression in breast cancer cells. It also profilesTRIB1-associated proteins in breast cancer cells, demonstrating conservation of TRIB1’s canonical interaction with COP1 and reveals associations with members of the wider ubiquitination machinery, a range of transcriptional regulators and chromatin remodelers. The data presented provide insight into the function of TRIB1 in breast cancer and the role of TRIB1 in transcriptional regulation.