Abstract P1-04-09: Essential role for MUC1-C in chronic activation of cytosolic nucleotide sensing and the type I interferon pathway in triple-negative breast cancer

Abstract

Abstract The MUC1-C transmembrane protein, which is aberrantly expressed in triple-negative breast cancer (TNBC), evolved in mammals to provide protection of epithelia from the external environment. MUC1-C functions as an effector of epithelial cell responses to inflammation and damage. MUC1-C induces inflammatory, proliferative and remodeling signaling pathways that are associated with wound healing. However, in contrast, prolonged MUC1-C activation in settings of chronic inflammation promotes cancer progression. Recent work has demonstrated that MUC1-C drives intrinsic activation of inflammatory signaling pathways in TNBC cells that are linked to immune evasion and oncogenesis (Yamashita N, JITC, 2021). By extension, what is needed now is a better understanding of how MUC1-C specifically integrates inflammation with TNBC progression. In addressing this issue, the present work uncovers a previously unrecognized MUC1-C activated inflammatory pathway that contributes to genomic instability and DNA damage tolerance in TNBC cells. Constitutive expression of pattern-recognition receptors (PRRs), which include the retinoic acid-inducible gene-1 (RIG-I/DDX58) and melanoma differentiation-associated gene 5 (MDA5/IFIH1), are activated by the presence of cytosolic dsRNA. Accumulation of DNA damage-associated molecular patterns (DAMPs) in the cytosol is recognized by activation of the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Stimulation of these RNA and DNA PRRs induces production of the type I IFNs and induction of interferon-stimulated genes (ISGs) that confer DNA damage resistance. We report here that MUC1-C is necessary for constitutive activation of RIG-I, MDA5, cGAS and STING in BRCA wild type and mutant TNBC cells. Consistent with these findings, we show that MUC1-C is necessary for expression of the downstream STAT1, STAT2 and IRF9 effectors in activation of the type I IFN pathway and the IFN-related DNA damage resistance gene signature (IRDS). One of the MUC1-C-induced IRDS genes encodes ISG15, a ubiquitin-like protein that links chronic inflammation and DNA damage resistance. Of translational significance, studies in TNBC cells treated with carboplatin or the PARP inhibitor olaparib demonstrate that MUC1-C is necessary for expression of RIG-I, MDA5, cGAS, STING and ISG15 and that targeting MUC1-C abrogates this response. In addition, we show that MUC1 significantly associates with the upregulation of STING, STAT1, STAT2, IRF9 and ISG15 in TNBC tumors. In summary, these findings in TNBC uncover an essential role for MUC1-C in chronic activation of the PRR/STING axis, type I IFN pathway and IRDS in association with conferring resistance to replicative stress. Our findings also support MUC1-C as a target for inhibiting DNA damage tolerance and synergistically sensitizing BRCA wild type and mutant TNBC cells to platinum-based agents and olaparib. Citation Format: Nami Yamashita, Atsushi Fushimi, Yoshihiro Morimoto, Atrayee Bhattacharya, Mark Long, Song Liu, Donald Kufe. Essential role for MUC1-C in chronic activation of cytosolic nucleotide sensing and the type I interferon pathway in triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-04-09.