Fig. 8: MUC1-C→SET1A/WDR5 COMPASS signaling in TNBC tumors associates with poor clinical outcomes and in TNBC cells confers cancer progression.

a GEPIA2 analysis of MUC1, WDR5 and SET1A expression in 135 TNBC tumors from the TCGA-BRCA RNA-seq dataset as compared to normal breast tissue from TCGA and GTEx. The P value was set to 0.05. b–d Relapse-free survival in patients with TNBC tumors expressing high vs low levels of MUC1 (b), WDR5 (c) and SET1A (d). e MUC1-C binds directly to NF-κB p65 and contributes to the activation of NF-κB p65 target genes, such as EZH2 and SUZ12, that encode components of the PRC2 complex. The present work demonstrates that MUC1-C/NF-κB occupy the SET1A and WDR5 genes at PLSs and are necessary for SET1A and WDR5 expression. WDR5 is indispensable for SET1A complex assembly and HMT activity. Our results show that (i) MUC1-C associates with SET1A and WDR5, and (ii) MUC1-C, NF-κB, SET1A and WDR5 occupy the AP-1 encoding FOS and ATF3 genes in association with increases in H3K4me3 and their expression. Of interest in this regard, FOS and ATF3 are activated by inflammatory stress in a potential feedback pathway that contributes to the activation of NF-κB and this COMPASS-associated pathway. In support of this notion, MUC1-C/NF-κB complexes associate with SET1A, WDR5 and AP-1 on target genes, such as TRAF1 and RELB, in the TNF→NF-κB pathway that drives chronic inflammation in cancer cells. We also found that (i) MUC1-C/NF-κB associates with SET1A, WDR5 and AP-1 on KLF4 and NOTCH1, and (ii) this complex is necessary for H3K4me3 deposition and their expression. These findings collectively support a model in which MUC1-C-induced activation of the SET1A/WDR5 COMPASS complex integrates inflammatory memory with the CSC state.