The Impact of Pleiotrophin on Breast Cancer Progression




Sorrelle, Noah Bruce

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Breast cancer is the most frequent type of cancer, despite being largely restricted to women. Over the past few decades, cancer biologists have made great strides in understanding the factors that drive breast cancer tumorigenesis and progression. However, the significance of many factors, such as Pleiotrophin, remain uncharacterized. Pleiotrophin (Ptn), a neurite outgrowth factor and a heparin-binding cytokine, is reportedly expressed in many types of cancer, including breast cancer. Despite being identified as a secreted factor produced by breast cancer cells in 1991, its functional significance in breast cancer is uncertain. Previous studies into this question were limited by available tools for specifically perturbing or knocking out Ptn genetically. Further, they were also limited in scope, focusing only on select characteristics of the tumor progression and the microenvironment. Curiously, research into Ptn's impact in breast cancer came to a halt in 2007, leaving the very question of Ptn's functional significance unanswered. Using pharmacologic and genetic methods, I tested the impact of Ptn perturbation in multiple preclinical models of breast cancer. Ptn perturbation only impacted primary tumor growth in a single model. In contrast, Ptn perturbation resulted in reduced pulmonary metastatic burden in every model tested thus far. This effect does not appear to be due to Ptn's direct impact on cancer cell phenotype, growth, or migration. Anti-Ptn therapy did not affect epithelial-tomesenchymal transition of cancer cells, nor did Ptn directly promote cancer cell proliferation or migration in vitro. These results suggest that Ptn's effects are through changes in the tumor microenvironment. By immunohistochemistry and flow cytometry, I observed that there was less neutrophil infiltration and macrophage/metastatic lesion coupling in vivo. This result was interesting as both neutrophils and macrophages are implicated in promoting pulmonary metastasis in preclinical models of breast cancer. Using a cytokine/chemokine array, I observed that Ptn perturbation resulted in the reduction of macrophage and neutrophil chemokines, including MCP-1 and CXCL5, respectively. In contrast to previous reports, Ptn perturbation did not result in changes in angiogenesis, epithelial-to-mesenchymal transition, or markers of cell proliferation or apoptosis. Some of these reported activities may have resulted from off-target effects of the tools used at the time. Overall, the experimental strategies and specificity of the tools used in my thesis work have provided more accurate insights into the activity of Ptn. Additionally, the results suggest that Ptn is a potent driver of pulmonary metastasis in breast cancer and that targeting Ptn may an effective therapeutic strategy to treat metastatic breast cancer.

General Notes

Page xiv is misnumbered as page xv.

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