Date of Award

2015

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

Marvella E. Ford

Fourth Advisor

Amanda C. LaRue

Fifth Advisor

Robin C. Muise-Helmericks

Abstract

In South Carolina, mortality differences between African American (AA) and Caucasian-American (CA) women with breast cancer are amongst the highest in the country. Increasing evidence suggests that the racial disparity exists independent of socioeconomic and standard of care issues and could also be attributed to poorly understood inherent genetic and molecular characteristics within racial specific tumors. Caveolin-1 (Cav1) is a scaffolding protein with a tumor suppressor role. Loss of Cav1 in the tumor stromal compartment has emerged as a novel biomarker for predicting poor clinical outcome in all of the most common subtypes of breast cancer. While the loss of stromal Cav1 is becoming well established as a marker of poor outcome in breast cancer, the mechanism of this loss is still unknown. We propose that differences in microRNA mediated stromal Cav1 loss between AA and CA women are driving the racial disparity in breast cancer. MicroRNAs (miRNAs) are short, endogenous, non-coding RNAs that function as negative regulators of gene expression. miR-510 is an oncogenic miRNA that has been shown to be elevated in breast tumors. Cav1 is a predicted target of miR-510; therefore, miR-510 mediated negative regulation may be a novel mechanism of Cav1 loss in the tumor stroma. Our research shows that Cav1 is directly targeted by miR-510 by luciferase reporter assay and that overexpression of miR-510 leads to downregulation of Cav1 protein expression, specifically in the stromal compartment. This may be racially significant as our supporting studies also show that miR-510 levels are elevated and Cav1 levels are reduced in AA breast cancer patients compared to their CA counterparts. Data from our in vivo studies shows that tumors grown from co-injection of MDA-MB-231 cells plus miR-510 derived fibroblasts resulted in faster tumor growth and larger tumors at the end of the study than tumors grown from injection of MDA-MB-231 cells alone, suggesting that miR-510 derived fibroblasts enhance tumorigenicity when co-injected with breast tumor epithelial cells. Our results suggest that the difference in miR-510 mediated regulation of stromal Cav1 is driving racial disparity in breast cancer.

Rights

All rights reserved. Copyright is held by the author.

Download

Share

COinS