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Elucidating the role of SOX4 in basal-like breast cancer tumorigenesis
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Khanna, Pooja. Elucidating the role of SOX4 in basal-like breast cancer tumorigenesis. Retrieved from https://doi.org/doi:10.7282/t3-95zr-fs19

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TitleElucidating the role of SOX4 in basal-like breast cancer tumorigenesis
NameKhanna, Pooja (author); Gatza, Michael (chair); Walworth, Nancy (member); Ganesan, Shridar (member); Hu, Wenwei (member); Pine, Sharon (member); Rutgers University; School of Graduate Studies
Date Created2022
Other Date2022-05 (degree)
SubjectBiology, Breast -- Cancer -- Genetic aspects
Extent226 pages : illustrations
DescriptionBreast cancer is the most commonly diagnosed cancer in women worldwide and a global health concern. Clinically, breast cancers are classified on the basis of estrogen, progesterone and HER2 amplification, which also function as druggable targets. Triple negative breast cancers lack these markers and thus have limited specific therapeutic options. Triple negative breast cancers, largely synonymous with the basal-like molecular subtype of breast cancer, have the highest rate of relapse and lowest survival rate of any breast cancer subtype. While progress has been made on treatments for other subtypes, there is still an urgent need for more targeted treatment options for triple negative breast cancers. SOX4 is an oncogenic transcription factor that is overexpressed in basal-like breast cancer and is associated with poor patient prognosis and high tumor grade. SOX4 has the ability to mediate multiple tumorigenic phenotypes in basal-like cancers, but the impact of SOX4 dysregulation on basal-like breast cancer signalosome has not been fully elucidated. As a transcription factor located in the nucleus, SOX4 is difficult to target directly and is unable to remodel chromatin accessibility without association with cofactors. We determined that SOX4 functions to transcriptionally upregulate expression of its cofactor, the Swi/Snf complex ATPase SMARCA4, in order to modulate down-stream signaling pathways including glycolysis, proliferation and the cell cycle.
Though triple negative breast cancer cells have high glycolytic activity, which in turn fuels cancer cell growth, the mechanism driving these changes was not previously understood. SOX4 and SMARCA4 are able to modulate glycolysis by binding to the promoter of Hexokinase 2, the first rate-limiting enzyme in the glycolytic pathway, which then drives glycolysis and down-stream proliferation. These studies identified a novel mechanism of glycolytic regulation in basal-like breast cancers.
We further demonstrated that SOX4 and SMARCA4 were able to modulate proliferation by regulating the cell cycle rather than apoptosis. In addition, we identified a novel pathway by which SOX4 could regulate metastasis and the epithelial-to-mesenchymal transition. SOX4 was able to modulate expression of Focal Adhesion Kinase (FAK), an interaction that has not been previously defined. Furthermore, we determined that SOX4 could negatively regulate beta-catenin expression, providing insight into the role of Wnt signaling in basal-like cancers. These studies determined previously unknown mechanisms of SOX4’s regulation of glycolysis, proliferation and metastasis and identified targeted therapeutic agents for triple negative breast cancer patients.
NotePh.D.
NoteIncludes bibliographical references
Genretheses
Persistent URLhttps://doi.org/doi:10.7282/t3-95zr-fs19
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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