Elucidating the role of the Fes tyrosine kinase in breast cancer
Fes was first discovered as a protein-tyrosine kinase-encoded by the v-fes retroviral oncogene. Retrovirally encoded Fes oncoproteins induced tumors in chickens and cats and cause tumors in transgenic mice; however, a role for Fes in human cancer has not been established. This thesis identifies tumo...
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| Language: | en en |
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2013
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| Online Access: | http://hdl.handle.net/1974/8527 |
| Summary: | Fes was first discovered as a protein-tyrosine kinase-encoded by the v-fes retroviral oncogene. Retrovirally encoded Fes oncoproteins induced tumors in chickens and cats and cause tumors in transgenic mice; however, a role for Fes in human cancer has not been established. This thesis identifies tumor promoting roles of Fes through effects on stromal cells using genetic mouse models. First, in an orthotopic mouse mammary gland engraftment model, I found that loss of Fes in the host correlated with reductions in engrafted tumor growth rates, metastasis and circulating tumor cells, which may be partly due to reduced vascularity and fewer tumor-associated macrophages. We also showed Fes-deficient macrophages were less capable of promoting tumor cell invasion in co-culture experiments. Next, I observed delayed tumor onset in the absence of Fes in a transgenic mouse model of breast cancer driven by an activated HER2/Neu allele. This longer tumor latency correlated with hyperinflammatory status of Fes-deficient normal mammary glands. Taken together, these observations argue that Fes inhibition might provide therapeutic benefits in breast cancer, by attenuating tumor-associated angiogenesis and the metastasis-promoting functions of tumor-associated macrophages, or by delaying breast tumor onset in women with HER2 overexpression.
Finally, we showed that mice engrafted with IL-4 producing tumor cells developed tumors with significantly reduced growth rates and a complete attenuation of lung metastasis, which correlated with increased numbers of macrophages and enhanced phagocytic capability of macrophages in the tumor microenvironment. These observations suggest that IL-4 could be a good candidate for immunotherapy. === Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2013-12-18 11:44:40.294 |
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