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Please use this identifier to cite or link to this item: http://hdl.handle.net/11375/10793
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dc.contributor.advisorHassell, John A.en_US
dc.contributor.advisorSheila K. Singh, Gerry D. Wrighten_US
dc.contributor.advisorSheila K. Singh, Gerry D. Wrighten_US
dc.contributor.authorGiacomelli, Andrew O.en_US
dc.date.accessioned2014-06-18T16:52:35Z-
dc.date.available2014-06-18T16:52:35Z-
dc.date.created2011-08-09en_US
dc.date.issued2011-10en_US
dc.identifier.otheropendissertations/5814en_US
dc.identifier.other6817en_US
dc.identifier.other2144118en_US
dc.identifier.urihttp://hdl.handle.net/11375/10793-
dc.description.abstract<p><strong>A growing body of evidence suggests that most human tumors, including those of the breast, are organized as cellular hierarchies. Positioned at the apex of these hierarchies are tumor-initiating cells (TICs), which are capable of limitless self-renewal and also differentiate, to give rise to various populations of non-tumorigenic cells that make up the bulk of the tumor. Importantly, recent findings have demonstrated that TICs are refractory to current best practice therapies, and thus likely account for high rates of tumor recurrence following remission. Therefore, it will likely be important to identify novel means of targeting TICs in order to achieve durable cancer cures.</strong></p> <p><strong>Using a highly sensitive transplantation assay, our laboratory previously showed that mammary tumors arising in various strains of transgenic mice comprise a very high fraction of TICs, and that when cells from these tumors are propagated in serum-free medium as tumorspheres, the high frequency of TICs is maintained. We therefore sought to use mouse mammary tumorspheres as an <em>in vitro</em> system with which to identify TIC-targeted agents and carried out a high-throughput screen of nearly 32,000 small molecules. To eliminate compounds showing general toxicity, we employed mouse mammospheres, which primarily comprise normal mammary epithelial stem and progenitor cells, in a secondary screen. Using this platform, we identified a small molecule that selectively targeted tumorsphere-derived cells <em>in vitro</em> and led to tumor growth arrest and tumor cell death <em>in vivo</em>. This study illustrates the utility of mouse models and high throughput screening to identify compounds which may target TICs but spare untransformed stem cells.</strong></p>en_US
dc.subjectBreast Canceren_US
dc.subjectDrug Discoveryen_US
dc.subjectHigh-Thoughput Screeningen_US
dc.subjectCancer Stem Cellsen_US
dc.subjectCancer Biologyen_US
dc.subjectChemicals and Drugsen_US
dc.subjectCancer Biologyen_US
dc.titleA HIGH-THROUGHPUT SCREEN TO IDENTIFY SMALL MOLECULES THAT SELECTIVELY TARGET TUMOR-INITIATING CELLS IN A MOUSE MODEL OF HER2-INDUCED BREAST CANCERen_US
dc.typethesisen_US
dc.contributor.departmentBiochemistryen_US
dc.description.degreeMaster of Science (MSc)en_US
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