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Advisory Committee Chair

Trygve O Tollefsbol

Advisory Committee Members

Andra Frost

Danny Welch

R Douglas Watson

Thane Wibbels

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Cell culture models of oncogenesis that use cellular reprogramming to generate a neoplastic cell from a normal cell provide one of the few opportunities to study the early stages of breast cancer development. Human mammary epithelial cells (HMECs) were induced to undergo a neoplastic transformation using defined genetic elements to generate transformed HMECs (THMECs). We conducted proteomic and transcriptomic analysis of three points in the neoplastic progression of breast cancer. First we monitored alterations in the proteome that revealed a progressive trend towards a metastatic state. Next, we identified a set of genes from transcriptomic analysis that displayed this same type of progressive trend and using pathway analysis illustrated that a portion of these genes have been shown to be regulated by hepatocyte nuclear factor 4a (HNF4a). We also illustrated using network analysis that HNF4a is associated with a large number of genes expressed in breast cancer brain metastasis. Lastly, from our transcriptomic data we identified 63 epigenetic modulating enzymes that are differentially expressed following hRASV12 introduction. The differential expression of epigenetic modulators on a global level may be an initial event in oncogenesis. Future studies will be aimed at identifying the exact role of HNF4a in breast cancer metastasis, understanding the effect of drastic alterations in the expression of epigenetic modulators and its role in oncogenesis, and elucidation of the differences at the genomic and transcriptomic levels of THMEC cells and very small embryonic like stem cells.

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