Date of Award

2015

Embargo Period

8-1-2024

Document Type

Thesis

Degree Name

Master of Biomedical Science

Department

Pathology and Laboratory Medicine

College

College of Graduate Studies

First Advisor

David P. Turner

Second Advisor

Victoria J. Findlay

Third Advisor

Laura Spruill

Fourth Advisor

Steven A. Rosenzweig

Abstract

Breast cancer is a heterogeneous disease that affects close to two million women each year. Of these women, seventy percent express estrogen receptor alpha, a member of the nuclear receptor subfamily that is activated in response to estrogen. Our research has shown an alternate mechanism by which estrogen receptor alpha is activated and subsequently elicits its cancer promoting effects. The process of glycation involves the non-enzymatic addition of sugar moieties to biological macromolecules which produce reactive metabolites known as advanced glycation end products (AGEs). These metabolites have been shown to be responsible for many of the complications associated with diabetes because of their ability to interact with the Receptor for Advanced Glycation End Products (RAGE) and produce a chronic inflammatory phenotype. Similarly, this same effect has been shown in several different cancers including prostate, melanoma, and colorectal. Like other cancers, we observed greater levels of AGEs and RAGE within breast cancer tumor and serum samples and showed a correlation between tumor progression and intratumoral AGE concentration. Utilizing two ER positive breast cancer cell lines, T47D and MCF7, we have also identified a role for AGEs in the phosphorylation of the estrogen receptor at two different residues within the ligand independent activation domain: serine 118 and serine 167. By utilizing exogenous AGE treatment and inhibition with molecular inhibitors, we showed that, following exposure to AGEs, a signaling cascade occurs through Akt and ERK to phosphorylate these two residues. Additionally, this signaling pathway produced a more proliferative phenotype in our cell lines. We were able to verify that AGE treatment was inducing this increase in proliferation through interaction with RAGE by using shRNA technology. Activation of the estrogen receptor at these particular residues has been shown to be indicative of tamoxifen resistance. We identified a role for AGEs in tamoxifen resistance by performing a cell viability assay and found that AGE treated cells were indeed less sensitive to drug treatment. Elucidating a role for AGE-RAGE signaling in breast cancer creates potential for improved therapies and preventative interventions for patients with the disease.

Rights

All rights reserved. Copyright is held by the author.

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