Nur77 Represses The Expression Of CD36 And FABP4 To Hamper Fatty Acid Uptake And Suppresses Breast Cancer Progression

Breast cancer is the most common cancer and the second leading cause of cancerrelated death in women worldwide.The molecular and prognostic heterogeneity present great challenges for cancer treatment.Nuclear receptor Nur77,through regulating metabolism reprogramming,plays paradoxical roles in tumorigeneses.Herein,we demonstrated that a knockout of Nur77 stimulated mammary tumor development in spontaneous MMTV-PyVT and chemically-induced(MPA-DMBA-treated)mouse models,while a re-expression of Nur77 specifically in mammary tissue of Nur77-KO mice retarded tumor progression.Further research indicated that there were more abundant lipid droplets in proliferating cells in PyVT-KO tumor sample than in PyVT-WT tumor sample.Meanwhile,Nur77 deficiency facilitates the uptake of exogenous fatty acids by breast cancer cells for rapid proliferation,which was verified by performing in co-culture experiments.To globally evaluate the influence of Nur77 on gene expression in mammary tumor,primary tumor cells from either PyVT-WT or PyVT-KO tumor samples were collected for RNA sequencing(RNA-seq).Gene set enrichment analysis(GSEA)of RNA-seq data demonstrated that Nur77 may play an inhibitory role in fatty acid uptake in mammary tumor.Notably,CD36 and FABP4,which have been reported to be involved in cellular uptake and transport of fatty acids,were among the most obvious genes down-regulated by Nur77.In order to explain how the protein expression of Nur77 was gradually decreased with the development of breast cancer,it was Nur77 that interacted with PPARy by silver staining and mass spectrometry-based analysis.In this process,nuclear receptor PPAR? plays a counteracting role by binding to Nur77 for a Trim 13-mediated ubiquitination and degradation.Nur77 represses the transcriptions of CD36 and FABP4 to hamper fatty acid uptake,thereby leading to the inhibition of breast cancer cells'proliferation.Nevertheless,this role of Nur77 was nullified during breast cancer progression due to highly expressed nuclear receptor PP ARy that interacted with Nur77 to recruit ubiquitin ligase Trim13 to target Nur77 for degradation.This study demonstrates that Nur77 can serve as an intervention target for breast cancer,and the interference on PPAR?-Nur77 interaction may provide an opportunity to arrest breast cancer progression.