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    The cJun NH2-Terminal Kinase Pathway in HER2+ Breast Cancer Development and Inflammation

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    Name:
    ZeynepItah_PhDThesis.pdf
    Embargo:
    2024-01-12
    Size:
    31.49Mb
    Format:
    PDF
    Description:
    PhD thesis
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    Authors
    Itah, Zeynep cc
    Faculty Advisor
    Roger J. Davis
    Academic Program
    Interdisciplinary
    UMass Chan Affiliations
    Program in Molecular Medicine
    Document Type
    Doctoral Dissertation
    Publication Date
    2022-12-20
    Keywords
    JNK
    HER2
    SPLICOFORM
    INFLAMMATION
    breast cancer
    
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    Abstract
    The 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.
    DOI
    10.13028/6yb2-xg39
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/51564
    Rights
    Copyright © 2022 Itah
    Distribution License
    All Rights Reserved
    ae974a485f413a2113503eed53cd6c53
    10.13028/6yb2-xg39
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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