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Targeting the Janus Kinase Pathway in Tumor Associated Macrophages in Breast Cancer [electronic resource]

University of Minnesota. Pharmacology.

[S.l.] : University of Minnesota. 2023 Ann Arbor : ProQuest Dissertations & Theses , 2023

1 online resource(157 p.)

Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
Advisor: Schwertfeger, Kathryn L.

Thesis (Ph.D.)--University of Minnesota, 2023.

Interactions between tumor cells and the tumor microenvironment are critical for tumor growth, progression, and response to therapy. Effective targeting of oncogenic signaling pathways in tumors requires an understanding of how these therapies impact both tumor cells and cells within the tumor microenvironment. One such pathway is the Janus kinase (JAK)/signal transducer and activator or transcription (STAT) pathway, which is activated in both breast cancer cells and in tumor associated macrophages. Inhibitors for the JAK/STAT pathway are currently being investigated to 'turn off' the oncogenic signaling in the tumor cells. The studies performed in this dissertation aim to investigate the role of the JAK/STAT pathway in cells of the tumor microenvironment, specifically the tumor-associated macrophages. We have demonstrated that exposure of macrophages to JAK inhibitors leads to activation of NF-κB signaling, which results in increased expression of genes known to be associated with therapeutic resistance. Furthermore, inhibition of the NF-κB pathway improves the ability of ruxolitinib to reduce mammary tumor growth in vivo. We have further investigated the role of STAT5 in macrophages, and its contributions to mammary tumor progression and metastasis. We demonstrate that macrophages regulate the immune environment within the tumor in a STAT5 dependent manner and control metastasis of the primary tumor to distant sites. Thus, the impact of the tumor microenvironment is an important consideration in studying breast cancer and understanding such mechanisms of resistance is critical to development of effective targeted therapies.

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