Abstract 4338: The lipogenic phenotype of HER2/neu-positive breast cancer cells

Abstract

Abstract 15 - 30 % of all breast cancer cases are classified as HER2/neu-positive, a very aggressive form of breast cancer that correlates with a poor prognosis, reduced survival time and increased incidence of metastasis. We have shown that the HER2-positive breast cancer cell line BT474 relies on a unique Warburg-like metabolism for survival and aggressive behavior. These cells are dependent on fatty acid synthesis, presumably as a means to regenerate NAD+ for aerobic glycolysis. The cells show markedly increased levels of stored fats compared to other breast cancer cell lines and disruption of the synthetic process results in apoptosis. This metabolic phenotype is operating at its limits in HER2-positive cells, as addition of exogenous palmitate results in cell death, whereas HER2-normal cells are not affected by this treatment. Microarray analysis of palmitate-treated HER2/neu-positive SKBR3 cells and HER2-normal MCF7 cells suggests that palmitate induces an ER-stress response in the HER2-positive cells. This is congruent with protein markers for stress-related translational stalling, which ultimately result in CHOP-dependent cell death. Palmitate distinctly reduces the expression of the HER3 protein and combination treatments with palmitate and HER2-targeted therapeutic compounds show synergistic effects and markedly increase the cytotoxic effects of either compound alone. In addition to these translational changes, palmitate treatment of HER2/neu-positive SKBR3 cells results in AMPK activation and subsequent inhibition of fatty acid synthesis. Transcriptome and global metabolite profiling analyses of the effect of increased palmitate on these cells indicate that palmitate alters the metabolic phenotype by re-routing the glucose carbon flux in the cells. Supported by CDMRP Award W81XWH-11-1-0094 to Jan Baumann and NCI Award 5R01CA136658-03 to Douglas Conklin. Citation Format: Jan M. Baumann, Douglas S. Conklin. The lipogenic phenotype of HER2/neu-positive breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4338. doi:10.1158/1538-7445.AM2014-4338