All ETDs from UAB

Advisory Committee Chair

Trygve O Tollefsbol

Advisory Committee Members

Stephen A Watts

Melissa Harris

Upender Manne

David Schneider

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

About 1 in 8 women will be diagnosed with breast cancer at some time in their lives, and more than 40,000 women will die due to breast cancer this year. Women do not die from localized breast cancer cases but from metastatic, or Stage IV, breast cancer (MBC). Over 150,000 women are currently living with MBC, and treatments focus on length and quality of life considering there is no cure. Triple-negative breast cancers (TNBC) do not respond to targeted therapies as they are lacking estrogen receptor alpha (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). They comprise approximately 15-20% of all breast cancer diagnoses, and triple-negative MBC cases can be a scary diagnosis since treatment options are limited. Preventing metastatic breast cancer while treating TNBC would be huge breakthrough. This project explores the effects of two epigenome-modifying compounds on TNBC and metastatic potential. Suberoylanilide hydroxamic acid (SAHA) is an FDA-approved chemotherapeutic agent and epigallocatechin-3-gallate (EGCG) is a green tea polyphenol. We investigated the mechanisms behind the increase in breast cancer cell death with SAHA and EGCG through the lens of metastatic potential and provide preliminary evidence that these two compounds in combination reduce growth of breast cancer cells. Our results show that despite the increase in cell death, there are different acting mechanisms, which places an emphasis on heterogeneity of TNBC. We demonstrate that SAHA and EGCG act through epigenetic mechanisms and reduce migration of the breast cancer cells. Also, SAHA and EGCG were capable of restoring p27 and PTEN expression and reducing the expression of miR-221/222 and cIAP2. We attribute these changes to modifications of the cancer epigenome induced by SAHA and EGCG.

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