Date of Award

2019

Document Type

Open Access Master's Thesis

Degree Name

Master of Science in Biological Sciences (MS)

Administrative Home Department

Department of Biological Sciences

Advisor 1

Xiaohu Tang

Committee Member 1

Ebenezer Tumban

Committee Member 2

Thomas Werner

Abstract

Breast cancer is a collection of heterogeneous diseases and the most common cancer in females worldwide. Breast cancer is often categorized by the distinctive expression of membrane biomarkers including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (Her2). Breast cancer has four main subtypes: luminal A, luminal B, basal-like, and HER2-positive. Of all breast cancer types, triple-negative breast cancer (TNBC) is the most aggressive metastatic subtype, accounting for 15~20% with the basal-like and claudin-low features, and lack of effective targeted therapies due to the absence of cell membrane receptors. In recent research, metabolic dysregulation has been noted as a hallmark of cancer, which can be used to design targeted therapies specific for a certain metabolic weakness of cancer. Cystine, the oxidized dimer of cysteine, is transported into the cell and a major source of glutathione (GSH), which maintains the cellular redox balance. Mesenchymal TNBC has been found to be cysteine-addictive/dependent and requires excess cystine to survive. Although limiting cellular cystine/cysteine is an efficient strategy to kill most of TNBC tumor cells, we observed that a portion of tumor cells remains to survive and expand after cellular cysteine depletion by erastin, an inhibitor of cystine transporter. This in vitro observation may substantially mimic tumor relapse in patients after targeted cysteine-addiction therapy. The three aims of this study are: 1) Develop in vitro erastin-resistant TNBC cell models; 2) Understand the underlying mechanisms of erastin-resistance; and 3) Identify potential sensitizers to overcome the erastin-resistance in tumor cells. First, we established three erastin-resistant cell systems derived from cystine-addictive TNBCs. Second, we identified potential combinative sensitizers to eradicate the erastin-resistant tumor cells by an epigenetic compound library screen approach. Last, we performed microarray gene expression profiling analysis and found distinct gene expression patterns between erastin-resistant and erastin-sensitive cells that will help uncover the underlying mechanism of erastin-resistance. Identification of combinative sensitizers and understanding the erastin resistance may help designing an optimal therapeutic strategy to prevent tumor recurrence in patients.

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