Abstract 1883: 2-Hydroxyglutarate: A candidate oncometabolite in breast cancer.

Abstract Recent work in our laboratory identified a poor outcome tumor subtype with a high tissue 2HG concentration, distinct genome-wide DNA methylation, and a stem cell-like transcriptional signature. Currently, we do not know the origin of 2HG in these tumors but ruled out that it is caused by acquired isocitrate dehydrogenase mutations. Tumors with high 2HG tended to be estrogen receptor (ER)-negative and were over-represented among the African-American patients. Additional investigations revealed that 2HG can accumulate in a subset of human breast cancer cell lines to 50- to 100-fold above the baseline in non-cancerous cells, reminiscent of the difference between 2HG-high tumors and their adjacent non-cancerous tissue. The majority of the 2HG-high cell lines showed basal-like characteristics. While some cancer cells had these highly increased 2HG levels, other cell lines did not accumulate 2HG, providing a model to study 2HG treatment effects in cell lines with low endogenous 2HG and to identify the origin of increased 2HG production in those cell lines with high endogenous 2HG. Thus, we tested the hypothesis that 2HG influences breast cancer phenotypes. These experiments showed that 2HG induced phenotypic alterations, DNA methylation pattern alterations, proliferation, increased invasion and migration, and EGFR pathway activation in breast epithelial cells consistent with its oncogenic function in breast cancer. However, the observed phenotypes were partly cell line- and dose-dependent in our short term assays. Our results also indicated that different subtypes of breast cancer cells may respond differentially to 2HG, which suggests that possibly different cellular pathways are activated by 2HG in the various subtypes. Citation Format: Prachi Mishra. 2-Hydroxyglutarate: A candidate oncometabolite in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1883. doi:10.1158/1538-7445.AM2013-1883