CHARACTERIZATION OF THE CANCER-ASSOCIATED EFFECTS OF LOSS AND/OR MUTATION OF TUMOR SUPPRESSOR GENES ON NF-kB SIGNALING IN BREAST AND PANCREATIC CANCERS

Despite available therapies, many ER+ breast cancer patients relapse with metastasis. In our study, we find approximately 30% of Luminal A breast cancer patients show low DAB2IP expression, leading to significantly reduced relapse-free survival. DAB2IP deficiency, mainly in higher grade tumors, correlates with increased phosphorylation of IKK, the kinase that regulates NF-B. Upregulated genes in DAB2IP-low Luminal A tumors overlap with aggressive subtypes, promoting proliferation, metastasis, and heightened ER signaling. ChIP-seq data show that DAB2IP loss in Luminal A cancer cells increases NF-B genomic binding, upregulating NF-B target genes linked to oncogenic traits like altered RNA processing. This study offers a new understanding of aggressiveness and recurrence in a subset of Luminal A breast cancers that are otherwise known for their less aggressiveness. Further, low DAB2IP in ER+ Luminal A breast tumors are enriched for non-classical estrogen and ESR1-regulated gene expression, affecting response to endocrine therapies. Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease due to poor early detection, aggressive nature, and therapy resistance. Approximately 70% of PDAC patients exhibit mutations or loss of p53. Gain-of-function phenotypes for mutant p53 are reported, but their mechanisms are unclear. This study explores the impact of NF-κB subunit c-REL on PDAC progression linked to mutant p53. RNA-sequencing revealed elevated c-REL expression in PDAC with mutant R172H p53 compared to wild-type or p53 null cells in mice and humans. Immunostaining revealed higher c-REL expression in grade 1 PDAC tumors compared to normal tissues. Using CPTAC human PDAC data, we confirmed increased c-REL levels with mutant p53 at transcriptomic and protein levels. High c- REL is linked to decreased overall survival in PDAC patients. From integrated ChIP-seq and RNA-seq data, we identified target genes regulated uniquely by c-REL in PDAC cells with mutant p53 versus wild-type p53 and p53 null cells. Genes upregulated by c-REL in mutant p53-specific PDAC cells are involved in proliferation and pro-tumorigenic signaling. Knockout of c-REL decreased mouse tumor size in the KPC/R172H model, altering the tumor microenvironment and promoting immunosuppression in PDAC. This study highlights the interaction between mutant p53 and c-REL, shedding light on how gain-of-function mutant p53 traits impact c-REL and ultimately contribute to aggressive PDAC. Inhibition of c-REL could potentially enhance immunotherapy against pancreatic cancer, addressing associated immunosuppression.