Date of Completion

11-30-2017

Embargo Period

11-29-2019

Keywords

Breast Cancer, EMT, Metabolic Reprogramming, Lactate Metabolism, MCT1, GPR81

Major Advisor

Bruce A. White

Associate Advisor

Molly A. Brewer

Associate Advisor

John R. Harrison

Associate Advisor

Lisa M. Mehlmann

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Lactate is both a metabolite of glycolysis, and a component of several signaling pathways. Although recent studies indicate that lactate is a critical regulator of cancer development, very little is known about lactate metabolism in the context of metastatic cancer. Epithelial-to mesenchymal transition (EMT) promotes metastasis by inducing invasive properties in epithelial tumors. To determine whether EMT induces metabolic alterations, we have studied two epithelial breast cancer cell lines and their respective EMT-induced mesenchymal progeny for changes in lactate metabolism. Metabolic analysis revealed that EMT induced an enhanced glycolytic profile in mesenchymal breast cancer cells. In contrast, epithelial breast cancer cells preferentially use oxidative phosphorylation (OXPHOS) to produce ATP. The strong expression of the lactate importer MCT1 in epithelial breast cancer cells may involve the ERα-inducible GATA3 transcription factor. We detected a specific GATA3 binding site in the DNAse-hypersensitive region within the promoter of MCT1 gene and found that knockdown of GATA3 represses MCT1 expression. We also observed that the endogenous lactate receptor, G-protein coupled receptor 81 (GPR81), was highly expressed in epithelial breast cancer cell lines and hormone-positive breast cancer tumors. GPR81 regulated MCT1 expression and lactate uptake in epithelial breast cancer cells and its expression was crucial for cell proliferation and survival under nutrient-limited conditions. This study provides an overview of specific metabolic changes induced by EMT in two independent and substantially different epithelial breast cancer cell lines. In addition, we propose GPR81 as a potential prognostic marker and therapeutic target in hormone positive epithelial breast cancer.

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