Abstract 1702: Metabolic heterogeneity of HER2-positive breast cancers.

Abstract

Abstract Breast cancers are at least five molecularly distinct diseases with reported metabolic differences. Basal-like breast cancers are typically more glycolytic as compared to luminal-like breast cancers. However, HER2-positive breast tumors have variable FDG-PET maximum uptake values. We hypothesized that HER2-positive breast cancer cell lines would reflect the metabolic heterogeneity reported in breast cancer tumors. In the current study, a panel of HER2-positive breast cancer cell lines (N = 8) was profiled by their metabolic properties. To evaluate glycolytic dependency for ATP production, ATP-synthase dependent oxygen consumption rates were normalized to extracellular acidification rates using the Seahorse Bioscience XF analyzer. The glycolytic dependency was highly variable (12-fold range); ER-negative lines including AU565 and HCC1954 were the most glycolytic. Consistent with these results, HER2-positive/ER-negative cell lines produced more lactate compared to HER2-positive/ER-positive cell lines (1.5 versus 1.2 lactate produced/glucose consumed, p = 0.02). The glycolytic phenotypes of HER2-positive/ER-negative breast cancer cell lines were similar to that of basal-like breast cancer cell lines. For the HER2-positive lines, the highest rates of glutamine consumption were in ER-positive lines BT474 and HCC1419. Differential expression of mitochondrial glutaminase 2 (GLS2, p = 0.02), but not cytosolic glutaminase (GLS) or glutamine synthetase (GLUL), may contribute to higher rates of glutamine consumption by HER2-positive/ER-positive breast cancers. Consistent with higher rates of mitochondrial respiration, ER-positive/HER2-positive cells were also associated with higher expression of carbonic anhydrase 12 (CA12) and lower expression of the lactate transporter MCT1 (SLC16A1). Metabolic heterogeneity of HER2-positive cells was only evident in normoxic conditions. Per the “Pasteur effect,” all cell lines cultured under hypoxia (1% O2) were equally glycolytic (average = 1.8 lactate production/glucose consumption ratio) with correspondingly reduced rates of glutamine uptake. We conclude that the heterogeneity observed in FDG-PET may be influenced by fundamental metabolic differences between HER2-positive breast cancers, in particular, for well-oxygenated regions of the tumor. Citation Format: Jennifer B. Dennison, Gordon B. Mills. Metabolic heterogeneity of HER2-positive breast cancers. [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 1702. doi:10.1158/1538-7445.AM2013-1702