Abstract LB-266: DAXX promotes de novo lipogenesis in triple-negative breast cancer

Abstract

Abstract Triple-negative breast cancers (TNBCs), defined by the absence of ER and PR expression and the lack of HER2 amplification, have no targeted treatment options, are highly aggressive, and exhibit poor prognosis. Identification of drivers and associated signaling pathways, particularly for TNBCs, is needed to assist the development of targeted therapies, to prolong disease-free survival, and to improve clinical outcome for cancer patients. Using high-throughput microarray-based global transcriptome profiling, we found that transcriptional regulator DAXX depletion strikingly impaired while DAXX overexpression enhanced the expression of genes in the de novo lipogenesis pathways in TNBCs cell line. Consistently, unbiased global metabolomics and lipidomics profiling by Ultra-High performance Liquid Chromatography coupled High-Resolution Mass Spectrometry (UHPLC-HRMS) also revealed that DAXX promotes de novo lipogenesis in both TNBC cell line as well as in corresponding xenograft tumors. In analyzing large number of genomic datasets including The Cancer Genome Atlas (TCGA), MolEcular Taxonomy of BReast cancer International Consortium (METABRIC), and The Cancer Cell Line Encyclopedia (CCLE) dataset, we found that DAXX expression is significantly higher in TNBC tumor samples and cell lines, and also DAXX gene expression positively correlates with that of key lipogenesis enzymes. The role of DAXX in cancer metabolism is previously unknown. Our integrated OMICs data analysis thus indicates that DAXX promotes de novo lipogenesis in TNBC. The mechanism through which DAXX regulates lipid metabolism is being investigated in our laboratory. Overall, our study identifies a potentially important pathway driving TNBC progression and suggests potential therapeutic targets for treating this aggressive form of breast cancer that still lacks curative treatment options. Citation Format: Iqbal Mahmud, Timothy J. Garrett, Daiqing Liao. DAXX promotes de novo lipogenesis in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-266. doi:10.1158/1538-7445.AM2017-LB-266