Fumarate, an Oncometabolite Is Elevated in ER- Breast Cancers from African-American Women
Ashwini K Esnakula, Tammey J Naab, Luisel J Ricks-Santi, Wayne AI Frederick, Robert L DeWitty, Jr., Yasmine Kanaan. Howard University Hospital, Washington, DC; Howard University College of Medicine, Washington, DC
Background: Estrogen receptor negative (ER-) breast cancer, which is associated with chemotherapy resistance and poorer survival, is more common in younger African-American women. The various genetic and epigenetic differences between ER - and ER+ breast cancers have been studied, but only rare studies have analyzed the dysregulated metabolic pathways between these two subtypes. Metabolomics, a study of cellular small-molecule metabolites, is used to analyze the metabolic differences between ER+ and ER- tumors. The goal of our study is to establish the metabolomic profile of biochemicals in various energy pathways in ER- and ER+ breast cancers from African-American women.
Design: Breast cancer tumor tissue methanol extracts from 15 ER- and 15 ER+ African-American women were analyzed using liquid/gas-chromatography coupled to mass spectrometry. Following log transformation and imputation with minimal observed values for each compound, Welch's two-sample t-test was used to identify metabolites that differed significantly between experimental groups. Statistical significance was assumed if P ≤ 0.05.
Results: ER- tumors when compared to ER + tumors showed significant increase in various intermediates of Tricarboxylic acid cycle (TCA or Krebs cycle) which include succinate, fumarate and malate. Fumarate levels were almost 8-fold higher in ER- tumors when compared to ER+ breast cancers. There was also significant increase in branched chain amino acids including aspartate, phenylalanine and methionine, all of which could contribute to substantial increase in fumarate.
Conclusions: Our study shows a substantial increase in fumarate in ER- tumors when compared to ER+ tumors. Fumarate has recently been identified as an oncometabolite. Intracellular accumulation of fumarate is associated with diverse consequences. Competitive inhibition of 2-oxygenase enzyme group leads to activation of oncogenic factors like hypoxia-inducible factors (HIF). Enhanced HIF-1α signaling is associated with tumor angiogenesis secondary to increased secretion of vascular endothelial growth factor (VEGF) by the cancer cells. Fumarate also mediates non enzymatic succination of various cellular proteins leading to dysregulation or loss of protein which also highlights the oncogenic potential of fumarate. Elevated levels of fumarate in ER- breast cancers could play an important role in the aggressiveness of ER- cases.
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 8, Tuesday Morning