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Breast tumorigenesis relies on complex interactions between tumor cells and their surrounding environment, orchestrated by tightly regulated transcriptional networks. While much is known about the signaling pathways affecting breast cancer cell growth and apoptosis, the transcriptional programs driving these responses are less understood. C/EBPβ is a transcription factor essential for proper cellular proliferation, differentiation, tissue function, metabolism, and the immune response, and is deregulated in breast cancer. C/EBPβ and its protein isoform LIP have long been postulated to promote breast cancer progression, however, the precise mechanisms and gene regulatory networks induced by C/EBPβ are less understood. Analysis of available human patient gene expression data reveals that increased Cebpb mRNA is associated with poor overall survival amongst all breast cancer subtypes, and analysis of available liquid chromatography with tandem mass spectrometry data shows that increased C/EBPβ total protein is associated with poor overall survival in triple-negative breast cancer patients. To test the function of C/EBPβ in tumor initiation and progression, several genetic mouse models were generated. Genetic ablation of tumor C/EBPβ in mouse models of basal-like [C3(1)TAg] and luminal (MMTV-Neu) breast cancers results in a complete block in mammary tumorigenesis. Interestingly, C/EBPβ-null tumor cells upregulate genes involved in antigen presentation and interferon gamma response in vitro, while overexpression of the C/EBPβ-LIP induces chemokines involved in immune cell recruitment and immunosuppression, such as CCL5. In support, RNA sequencing of human breast cancer cells shows that deletion of Cebpb in BT-20 cells causes de-repression of immune genes. Specifically, genes associated with interferon α and γ signaling (JAK1, TNFA, CCRL16, CSF2, IL32) as well as genes involved in antigen processing and presentation (MHC class I and class II molecules) are upregulated in the absence of Cebpb. These data suggest that C/EBPβ may repress genes important for immune visibility. Ongoing studies are aimed at identifying gene regulatory programs induced by C/EBPβ and specifically by C/EBPβ-LIP. These studies will have critical implications for whether C/EBPβ-induced pathways can be targeted in combination with other drugs, such as immune checkpoint inhibitors, improving patient outcome. These studies are supported by NIH RO1CA212518 (H.L.M.). Citation Format: Caitlin M. Burke, Michelle D. Rojo, Jeffery M. Rosen, Tobias Ackermann, Christine Muller, Cornelis F. Calkhoven, Heather L. Machado. C/EBPβis required for mouse mammary tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 915. |
