Molecular Mechanisms Underlying The Regulation Of Gene Expression And Growth In Breast Cancer Cells

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Breast cancer is a serious public health issue, and a full understanding of its etiology and pathophysiology is a primary focus in the field. Molecularly, the combined action of a plethora of factors in multiple pathways is involved in the regulation of the breast tumoriogenic process. Characterization of a more complete spectrum of the molecular factors will provide insights into the development of new and improved diagnostic, prognostic and therapeutic tools for treating breast cancer. To this end, my studies utilize a combination of molecular biology and bioinformatic methods, to uncover the mechanisms underlying the regulation of gene expression and growth in human breast cancer cells. To investigate the molecular crosstalk of the estrogen and c-Jun N-terminal kinase 1 (JNK1) signaling pathways, I monitored the genomic localization of estrogen receptor [alpha] (ER[alpha]) and JNK1 in basal and estrogen-stimulated MCF-7 breast cancer cells. I found that JNK1 binds to the promoter of many genes. ER[alpha] is required for the binding of JNK1 to the estrogen-induced sites, and JNK1 in turn functions as a coregulator of ER[alpha]. The convergence of ER[alpha] and JNK1 at target promoters regulates estrogen-dependent gene expression, as well as downstream estrogendependent cell growth responses. Furthermore, the implication of long noncoding RNAs (lncRNAs) in breast cancer is also coming to light. I developed a computational approach that integrates information from multiple genomic datasets, and generated a comprehensive catalog of 1888 expressed lncRNA genes in MCF-7 cells. Almost half of them are first annotated in this study, and more than a quarter are estrogen-regulated. Close examination revealed many interesting features. Interestingly, cell type-specific expression of lncRNAs predicts the intrinsic molecular subtypes of breast cancer, suggesting its potential utility as prognostic marker. Lastly, by selecting lncRNAs with elevated expression in breast tumors, and whose differential expression across a wide spectrum of tissues and cell types correlates with important cell viability genes, we identified a number of lncRNAs that are required for the normal growth of human breast cancer cells. Collectively, my studies expanded our understanding of the molecular mechanisms underlying breast cancer biology, and suggested new targets for therapeutic interventions.
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Lis, John T
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Pleiss, Jeffrey A.
Clark, Andrew
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Ph. D., Biochemistry
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Doctor of Philosophy
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dissertation or thesis
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