Metabolic heterogeneity in breast cancer
Breast cancer is the second leading cause of cancer deaths in women and hence understanding the pathophysiology of this disease is necessary to develop novel treatments. Metabolic heterogeneity with transfer of catabolites between fibroblasts and breast cancer epithelial cells occurs in breast, ovarian and prostate carcinomas. Metabolic heterogeneity promotes tumor growth and resistance to anticancer agents. Fibroblasts have high rates of autophagy, catabolism, glycolysis and excrete large amounts of lactate and glutamine. Conversely, cancer epithelial cells use lactate and glutamine at high rates as substrates of oxidative phosphorylation (OXPHOS) mitochondrial metabolism and are more resistant to autophagy. Glutamine is a crucial amino acid in cancer cell metabolism and is the most abundant amino acid in plasma. Glutamine is catabolized to alpha-ketoglutarate through glutaminolysis and enters the tricarboxylic acid (TCA) cycle and increases OXPHOS in proliferating cells. Glutaminolysis via glutamate leads to the generation of the antioxidant glutathione, which protects cells from oxidative stress induced apoptosis. Ammonia is also a by-product of glutamine catabolism, which is a diffusible inducer of autophagy. TIGAR is a 2,6 phospho-fructose bisphosphatase which reduces glycolysis and apoptosis in cells. TIGAR is highly expressed in the majority of human breast carcinoma cells. Breast cancer cells tend to have low glycolytic rates and high lactate and glutamine uptake and catabolism rates. The mechanisms by which stromal-epithelial metabolic heterogeneity promotes tumor growth are unknown and we don’t know the effects of modulators of glycolysis and catabolites such as glutamine and lactate on cancer growth. It is unknown if TIGAR modulates lactate and glutamine catabolism and mitochondrial OXPHOS. I hypothesized that TIGAR and catabolites such as glutamine and lactate might drive tight metabolic heterogeneity in breast cancer. I have discovered using cellular and animal models that glutamine increases mitochondrial biogenesis, decreases autophagy and protects breast cancer cells from apoptosis. Glutamine also induces a catabolic phenotype in cancer-associated fibroblasts (CAFs). TIGAR expression in carcinoma cells is induced by CAFs. TIGAR overexpression in carcinoma cells induces metabolic heterogeneity between breast carcinoma cells and CAFs. TIGAR in carcinoma cells induces lactate and glutamine catabolism markers and higher NADPH levels and reduces glycolysis in carcinoma cells while as TIGAR induces a glycolytic phenotype in fibroblasts when overexpressed in carcinoma cells. Finally, TIGAR overexpression in carcinoma cells increases tumor size and weight in orthotopic xenograft models of breast cancer.
Ko, Ying-Hui, "Metabolic heterogeneity in breast cancer" (2016). ETD Collection for Thomas Jefferson University. AAI10253381.