Background: Although the introduction of the HER2-specific humanized monoclonal antibody Trastuzumab (T) in clinical practice revolutionized the treatment of HER2-positive breast cancer (BC), about half of the T-treated patients do not benefit or become refractory after its administration. Despite different molecular tumor profiles significantly associated with T benefit were reported, the identification of a non invasive clinical approach to select patients responsive or not to T is still a clinical unmet task. We recently reported that mammary cancer cell lines derived from spontaneous nodules arisen in mice transgenic for the human d16HER2 splice variant (HER2-addicted) were significantly enriched in genes involved in glycolysis pathway versus those developed in mice transgenic for the human full-length HER2-positive (WTHER2) (HER2-non addicted) (1,2). Accordingly, the aim of our study was to define whether tumor lactate levels could reflect HER2 addiction and, in turn, T susceptibility. Methods: The metabolite content in murine and human HER2-positive cell lines and specimens was determined by quantitative Nuclear Magnetic Resonance (NMR) spectroscopy. The optical metabolic imaging that quantifies the levels of the anaerobic glycolysis-related metabolite nicotinamide adenine dinucleotide (NADH) and the aerobic metabolite flavin adenine dinucleotide (FAD) was represented by Optical redox ratio (NADH/FAD). The extracellular levels of lactate were calculated by blood gas analyzer. Results: The metabolic profile of HER2-addicted (MI6, MI7) versus -non-addicted (WTHER2_1, WTHER2_2) murine tumor cells revealed higher intracellular levels of metabolites associated to glycolysis in MI6 and MI7 cells versus WTHER2-positive cells. In keeping, also the evaluation of the metabolic profile of human HER2-positive BC cell lines classified as addicted (SKBR3 and BT474) or not (MDAMB453 and MDAMB361) to HER2-signaling (3) confirmed significant higher intracellular and extracellular levels of lactate in HER2-addicted versus -non-addicted cells. The extracellular levels of NADH and NADH/FAD ratio further sustained a significantly higher activity of an anaerobic metabolism in HER2-addicted cells. Noteworthy, the metabolic profile of 27 HER2-positive BC cases treated with T, classified as HER2-addicted or not on the basis of the activation status of d16HER2 (1), provided further evidence of significantly higher levels of lactate in tumors HER2-addicted. Conclusions: Overall, even if a dysregulated glucose metabolism is a tumor hallmark, our results provide relevant in vitro and in vivo evidences of the potential future non-invasive lactate detection as a possible biomarker of HER2-addiction and T-responsiveness. Supported by the Italian Ministry of Health and AIRC. References: 1) Castagnoli L et Al, Cancer Res 2014 2) Castagnoli L et Al ,Oncogene 2016 3) Shiu KK et Al, Oncogene 2014 Citation Format: Lorenzo Castagnoli, Egidio Iorio, Ada Koschorke, Cristina Ghirelli, Gianmauro Palombelli, Debora Giani, Matteo Dugo, Daniele Morelli, Rossella Canese, Elda Tagliabue, Serenella M. Pupa. Lactate production as a potential marker of HER2-addiction and Trastuzumab susceptibility [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 5428. doi:10.1158/1538-7445.AM2017-5428
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.