Abstract 1836: Triple negative breast cancer: Metabolomics and flux analysis to identify targets for drug development

Abstract

Abstract To date, no targeted therapies are clinically available to treat triple negative breast cancer (TNBC). This highly aggressive form of breast cancer (BCa) derives its name from the absence of estrogen receptor (ER+), progesterone receptor (PR+), and HER2/neu receptor (HER2+). These receptors are expressed in other subtypes of BCa (i.e. Luminal, HER2-enriched) and have been successfully targeted with therapeutics such as Tamoxifen and Herceptin. New therapeutics are needed to improve the prognosis for patients with TNBC. Metabolomics and metabolic flux analysis (MFA) were conducted to reveal differences in TNBC cell lines compared with hormone receptor-positive cell lines (ER+ and +/-HER2+) prior to and following treatment with chemotherapy drugs. Two triple-negative (MDA-MB-231 and MDA-MB-468) and two hormone-responsive (BT474 and MCF-7) cell lines were compared before and after treatment with Taxol®/Paclitaxel. The metabolic profiles were assessed using 1H NMR broad spectrum metabolomics, MFA using [U-13C]-glucose and [U-13C]-glutamine enriched media, and cytokine profiling of the media. Broad spectrum metabolomics analysis demonstrated differences in the metabolic profiles between the TNBC and hormone-responsive cell lines in the absence of treatment, with a higher level of amino acids (e.g. alanine, glutamate, glutamine, glutathione), short chain fatty acids (isobutyrate, β-hydroxybutyrate), and nucleotides and nucleotide sugars (ADP, ATP, UDP-glucose, UDP-glucuronate) in the TNBC cell lines. Further, MFA demonstrated that glucose utilization was greater in the TNBC cells (MDA-MB-468) compared to the hormone-responsive cells (MCF-7). In addition, 13C-labeled glycine and 13C-labeled glutathione were only observed in TNBC cell lines treated in the presence of [U-13C]-glucose. In response to Taxol treatment, more metabolites were altered in the hormone-responsive cell lines compared with the TNBC cells. Profiling of 80 inflammatory cytokines (RayBiotech arrays) also demonstrated different responses in secreted inflammatory signals following treatment. We observed significant upregulation in interleukins-4 and -16 in MDA-MB-468 cells, while there was a downregulation of osteoprotegerin in all four cell lines after treatment with Taxol. This approach holds promise for identifying biomarkers which may be leveraged for development of targeted treatments. Citation Format: Delisha A. Stewart, Jason Winnike, Susan McRitchie, Wimal Pathmasiri, Susan Sumner. Triple negative breast cancer: Metabolomics and flux analysis to identify targets for drug development. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1836. doi:10.1158/1538-7445.AM2015-1836