Date of Award

12-30-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Bioinformatics

First Advisor

Damir Herman

Abstract

As a subtype of breast cancer, Triple Negative Breast Cancer (TNBC) is characterized by a unique molecular profile, distinct patterns of metastasis and a very aggressive phenotype. Without viable, confirmed therapeutic targets, treatment of TNBC remains one of the most pressing clinical challenges. Hypothesis-driven research on TNBC has focused on a handful of molecules suspected of playing a role in the disease etiology and has yielded limited success. The mechanisms underlying the origin and development of this disease still remain unknown. This gap in understanding the molecular mechanisms in TNBC was critical for undertaking the following analysis of this disease. In this study, we applied a systems biology approach and analyzed TNBC cells on multiple molecular levels to explore the different aspects of tumor cells and to obtain maximum insights into the biology of this disease. High-throughput transcriptomic (RNA-Seq) and proteomic (tandem mass-spectrometry) sequencing technologies were particularly valuable for this type of exploratory research. Briefly, mRNAs and proteins from cancer and cancer-free surrounding tissue were extracted from clinical surgical breast specimens. Transcriptome analysis of TNBC revealed molecular differences in global gene expression profiles between cancer and cancer-free control samples. Furthermore, we assessed the extent to which the identified transcriptome features were translated into their corresponding proteins. We demonstrated that - while the correlation between the amount of transcribed genes and their cognate translated proteins was low - aberrations in pathways involved in lipid metabolism, immune response as well as cell and tissue structure were detected on both the transcriptome and proteome levels. Moreover, we identified significant activation of genes involved in the cytokine-cytokine receptor interaction pathway, which may explain the aggressive phenotype of TNBC. These molecular aberrations were independently validated in a larger cohort from a publicly available breast cancer dataset as well as experimentally by immunohistochemistry of primary human breast cancer. The molecular biomarkers identified in this research should be further explored to provide insights into the etiology of TNBC, especially since those biomarkers have a high potential to be translated into direct clinical applications and thus may be relevant for improving the outcomes for TNBC patients.

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