Roger J. DavisItah, Zeynep2023-01-122023-01-122022-12-2010.13028/6yb2-xg39https://hdl.handle.net/20.500.14038/51564The c-Jun NH2-terminal kinases (JNKs) respond to environmental stresses by mediating key cellular processes. Thus, JNK signaling may contribute to the etiology of cancer. Indeed, loss-of-function mutations in the JNK pathway are frequently detected in human breast cancer, yet the functionality of these mutations remains unclear. I tested the tumor suppressive role of JNK signaling in HER2-driven breast cancer. Genetic ablation of the JNK pathway in human mammary epithelial cells causes both HER2-driven transformation morphology and gene signatures in 3D culture. JNK-deficiency may synergize with HER2 activation through integrin signaling to promote breast cancer. Indeed, JNK pathway loss accelerates HER2+ mammary tumorigenesis in mice. In contrast, JNK in macrophages contributes to tumor development by promoting a pro-tumorigenic inflammatory microenvironment. There are ꭤ and β splicoforms of JNK1 and JNK2 proteins which have differences in substrate specificity. Inflammatory responses are coordinated by JNK splicoforms selectively. Transcriptional regulation by JNK in the inflammation response causes alterations in gene expression and chromatin accessibility in macrophages. JNK also cooperates with other mediators for gene specific transcriptional regulation of inflammatory response. Overall, I showed that JNK in macrophages is required for full inflammatory activation. In conclusion, the JNK pathway acts as a tumor suppressor in HER2+ breast cancer cells with its pro-tumorigenic potential in macrophages by promoting inflammatory environment. These findings are relevant to the successful design of breast cancer therapy using drugs that target the JNK signaling pathway.en-USCopyright © 2022 ItahAll Rights ReservedJNKHER2SPLICOFORMINFLAMMATIONbreast cancerDoctoral Dissertation0000-0002-6960-211X