Browsing by Subject "STAT3"

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    Contributions Of Signal Transducer And Activator Of Transcription 3 To Tumor And Immune Cell Functions In Breast Cancer
    (2016-10) Chuntova, Polly
    The studies presented in this thesis demonstrate a novel link between activation of the FGFR pathway, alterations of the tumor microenvironment and tumor immune response in mammary tumorigenesis. These studies are the first to demonstrate that FGFR signaling in epithelial cells leads to accumulation of the ECM component hyaluronan (HA) through increased production of pro-inflammatory cytokines and activation of the STAT3 pathway. Therapeutic inhibition of STAT3 in vivo reduced HA accumulation, which correlated with reduced tumor burden. Nonetheless, STAT3 inhibition did not result in tumor regression, suggesting that additional pro-tumorigenic mechanisms are able to sustain tumor growth. Previous work has shown that FGFR1 activation leads to rapid recruitment of macrophages with pro-tumorigenic functions. We hypothesized that as TAMs differentiate in the presence of FGFR1-driven IL-6 family of cytokines, the STAT3 signaling pathway would be activated and would influence TAM differentiation. Therefore, further studies focused on delineating the STAT3-dependent phenotype and function of mammary TAMs. Utilizing a mouse model of genetic STAT3 ablation within myeloid cells demonstrated decreased tumor latency and increased tumor growth rate in conditional-STAT3∆/∆ mice compared to control animals. These results provide evidence to the hypothesis that STAT3 activation in different tumor and immune cell populations can result in both pro- and anti-tumor phenotypes, and detailed understanding of these mechanisms is necessary for developing effective therapeutic approaches.
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    FGFR1-induced soluble factors promote mammary tumorigenesis and chemoresistance
    (2013-08) Bade, Lindsey Kay
    The fibroblast growth factor receptor (FGFR) family consists of four receptor tyrosine kinases that are known regulators of cellular processes such as proliferation, migration, survival, and angiogenesis. Anomalous expression or uncontrolled activation of these receptors or their ligands has been correlated with progression of various types of cancer, including breast cancer. Specifically, the chromosomal locus of FGFR1, 8p11-12, is found to be aberrantly amplified in approximately 10% of patients diagnosed with breast cancer. Patients who harbor the FGFR1 amplification do not respond well to current therapies and develop resistance to hormone-based therapies. Therefore, understanding the molecular mechanisms of how FGFR1 overexpression promotes tumorigenesis may provide insights into better targets for novel, more effective therapies. The work presented here shows that FGFR1 activation significantly upregulates expression of the ligands AREG and EREG at the transcript and protein levels both in vitro and in vivo, which then activate EGFR signaling. AREG is critical for normal ductal morphogenesis in the mammary gland and has also been linked to breast cancer progression. Studies examining AREG expression in human breast cancers have found AREG expression to significantly correlate with regional lymph node metastases, large tumor size, and high-grade tumors. While EREG promotes proliferation of several normal and cancerous cell types, the role of EREG has not been extensively characterized in the mammary gland. However, recent studies have demonstrated that EREG is a potent mediator of metastasis of breast cancer cells to the lung and that overexpression of EREG is an indicator of poor prognosis for inflammatory breast cancer patients. EGFR, a member of the ErbB receptor tyrosine kinase family, has been well studied in the mammary gland, and it is known that EGFR is required for normal mammary gland ductal morphogenesis. Alternatively, overexpression or constitutive activation of EGFR in the mammary gland has been linked to mammary tumorigenesis. Additionally, overexpression of EGFR in the breast is associated with recurrence of earlier stage breast cancers and decreased disease-free and overall survival in later stage breast cancer patients. Notably, we demonstrate that EGFR activation is at least in part required for FGFR1-induced proliferation and migration and ERK1/2 activation, as inhibition of EGFR with the small molecule kinase inhibitor erlotinib significantly blocks these processes. Moreover, we show that FGFR1 and EGFR are co-expressed in TNBC cell lines and that both FGFR1 and EGFR can mediate Doxorubicin chemoresistance. We further show that FGFR1 upregulates expression of the cytokine LIF, which then signals through gp130/JAK to activate STAT3 in vitro. Directly inhibiting either FGFR1 or STAT3 significantly reduces chemoresistance and increases apoptosis in vitro. Furthermore, inhibition of FGFR1 with the small molecule inhibitor PD173074 results in increased chemosensitivity and apoptosis in a mouse model of mammary tumorigenesis. These results are significant because they are the first to show that FGFR1 signals through EGFR and that FGFR1 mediates chemoresistance through activation of STAT3. This study furthers our understanding of FGFR1-amplified mammary tumorigenesis and presents alternative factors for targeted therapies for patients with FGFR1-amplified breast cancers.