Date of Award

2019

Embargo Period

7-23-2024

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Cell and Molecular Pharmacology and Experimental Therapeutics

College

College of Graduate Studies

First Advisor

Elizabeth Yeh

Second Advisor

Joe Blumer

Third Advisor

Stephen Ethier

Fourth Advisor

Philip Howe

Fifth Advisor

Steven Rosenzweig

Abstract

EGFR is commonly over-expressed in metastatic breast cancer, yet metastatic breast cancer is generally resistant to anti-EGFR therapies, and the mechanism for resistance to EGFR inhibitors in this setting is not fully understood. HUNK kinase is up-regulated in aggressive breast cancers and is thought to play a role in breast cancer metastasis. However, no studies have been conducted to examine a relationship between EGFR and HUNK in breast cancer metastasis. Our studies show that HUNK phosphorylates T654 on EGFR, enhancing receptor stability and downstream signaling. We found that increased phosphorylation of T654 EGFR correlates with increased stem-like characteristics, migration and invasion, and metastasis. Additionally, we found that HUNK promotes a pro-tumor tumor microenvironment through the polarization of macrophages into TAMs. Interestingly, we found that elevated HUNK and EGFR co-expression reduces overall survival, and phosphorylated T654 on EGFR is elevated in advanced stage EGFR+ breast cancer. Importantly, our results show that the pharmacological inhibition of HUNK impairs phosphorylation of T654 on EGFR that corresponds to decreased breast cancer metastasis. This study shows HUNK directly phosphorylates EGFR at T654 to promote breast cancer metastasis and is the first study to show that the phosphorylation of this site in EGFR regulates metastasis.

Rights

All rights reserved. Copyright is held by the author.

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Available for download on Tuesday, July 23, 2024

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