Date of Award

2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pathology and Laboratory Medicine

College

College of Graduate Studies

First Advisor

Stephen P. Ethier

Second Advisor

Robin C. Muise-Helmericks

Third Advisor

Amanda C. LaRue

Fourth Advisor

Victoria J. Findlay

Fifth Advisor

Elizabeth S. Yeh

Abstract

The goal of this research was to elucidate the individual and cooperative role of oncogenes within the frequently amplified 8p12-11 genomic locus which is known to predict poor prognosis and resistance to endocrine therapy in breast cancer. The role of specific oncogenes from the 8p11-12 amplicon in breast tumors is highlighted and the construction of expression constructs for future studies is described. Further exploration of the oncogenic role of Eukaryotic Initiation Factor 4E-Binding Protein (4EBP1, EIF4EBP1) showed 4EBP1 is often highly overexpressed in malignant tumors and is predicted as an essential driving gene in many cancer cell lines in vitro, so we hypothesized 4EBP1 was a driving oncogene in breast cancers. High 4EBP1 gene expression was associated with reduced relapse free patient survival across all breast tumor subtypes, including post treatment tumors. We found 4EBP1 was crucial to the proliferation of all breast cancer cell lines tested, but not normal cells, making it a prime therapeutic target. This is the first report showing 4EBP1 levels influence malignant estrogen receptor α (ER, ESR1) levels, and we also explored the levels of other influential cancer related genes including oncogenes within 8p11-12 which are known to influence ER. Applied data mining and a current clinical trial implied importance for 4EBP1 as a biomarker for therapeutic efficacy, so we explored mTOR inhibition in multiple cell culture models. It is likely 4EBP1 mediates upstream signaling from many known tumorigenic signaling cascades in adaptive and different ways thus it should be further explored and has much potential as a biomarker and target for breast cancer, especially endocrine resistant tumors.

Rights

All rights reserved. Copyright is held by the author.

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