Global RNA-seq identified FBXL8 as a novel E3 ligase which modulates tumor suppressors to promote BRCA advancement

The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation. The E3 ubiquitin ligase is known to subtly balance immune-overactivation and pro-tumorigenesis. Here, by global transcriptional profiling of BRCA patient tissues, we identified a signature expression profile of F-box factors, of which FBXL8 emerged as a novel key component of E3 ligase. Our ex vivo studies (n=1349) indicate that FBXL8 promotes tumorigenesis and its level escalates with BRCA advancement. Knockdown of FBXL8 caused: (i) accumulation of two tumor-suppressors,CCND2 and IRF5, suggesting their collaborative regulation of BRCA status, (ii) intrinsic apoptosis in BRCA, (iii) inhibition of cell migration and invasion and (iv) downregulation of cancer-promoting cytokines/ chemokines; all of these effects curtailed the tumor microenvironment and suppressed cancer progression. Our findings highlight the translational impact of exploiting FBXL8 and its interaction partners (CCND2 and IRF5) for developing anti-cancer strategies and potential therapeutics to limit BRCA progression.