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- W4310360171 abstract "Abstract The polybromo-1 (PBRM1) chromatin-targeting subunit of the SWI/SNF PBAF chromatin remodeling complex drives DNA damage resistance and immune evasion in certain cancer cells through mechanisms that remain unclear. STAT1 and IRF1 are essential effectors of type I and II IFN pathways. Here, we report that MUC1-C is necessary for PBRM1 expression and that it forms a nuclear complex with PBRM1 in triple-negative breast cancer (TNBC) cells. Analysis of global transcriptional (RNA-seq) and chromatin accessibility (ATAC-seq) profiles further demonstrated that MUC1-C and PBRM1 drive STAT1 and IRF1 expression by increasing chromatin accessibility of promoter-like signatures (PLS) on their respective genes. We also found that MUC1-C, PBRM1, and IRF1 increase the expression and chromatin accessibility on PLSs of the (i) type II IFN pathway IDO1 and WARS genes and (ii) type I IFN pathway RIG-I, MDA5, and ISG15 genes that collectively contribute to DNA damage resistance and immune evasion. In support of these results, targeting MUC1-C in wild-type BRCA TNBC cells enhanced carboplatin-induced DNA damage and the loss of self-renewal capacity. In addition, MUC1-C was necessary for DNA damage resistance, self-renewal, and tumorigenicity in olaparib-resistant BRCA1-mutant TNBC cells. Analysis of TNBC tumors corroborated that (i) MUC1 and PBRM1 are associated with decreased responsiveness to chemotherapy and (ii) MUC1-C expression is associated with the depletion of tumor-infiltrating lymphocytes (TIL). These findings demonstrate that MUC1-C activates PBRM1, and thereby chromatin remodeling of IFN-stimulated genes that promote chronic inflammation, DNA damage resistance, and immune evasion. Implications: MUC1-C is necessary for PBRM1-driven chromatin remodeling in chronic activation of IFN pathway genes that promote DNA damage resistance and immunosuppression." @default.
- W4310360171 created "2022-12-09" @default.
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- W4310360171 date "2022-11-29" @default.
- W4310360171 modified "2023-10-17" @default.
- W4310360171 title "MUC1-C Dictates PBRM1-Mediated Chronic Induction of Interferon Signaling, DNA Damage Resistance, and Immunosuppression in Triple-Negative Breast Cancer" @default.
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- W4310360171 doi "https://doi.org/10.1158/1541-7786.mcr-22-0772" @default.
- W4310360171 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36445328" @default.
- W4310360171 hasPublicationYear "2022" @default.
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