Abstract A81: Fuel switch from glucose to lactate is dependent on tumor size in triple-negative breast cancer

Abstract

Abstract Rationale: Glycolysis provides the main source of ATP in most cancers. In particular, studies with FDG-PET have revealed that triple negative breast cancer (TNBC) have higher levels of uptake compared to other subtypes which is in keeping with the clinical behavior of TNBC. There has been recent interest in the use of platinum-based chemotherapy to treat TNBC, however, there still remains a need for improved targeted agents due to frequent relapse. To maintain cell growth in cancer cells, the securement of energy source is important and to possess diverse energy producing pathways is clearly advantageous for its growth and survival. Our study here investigates lactate metabolism in TNBC, as the capability to switch from glucose to lactate fuelled mitochondrial oxidative phosphorylation (OXPHOS) provides a clear survival advantage and has the potential to reveal a new therapeutic strategy in this disease. We, therefore, hypothesized that fast growing tumor, which eventually forms greater mass, should have monocarboxylate transporter 1 and 4 (MCT1 and 4) expression as an alternative energy pathway to glycolysis in order to adopt their faster growth by changing energy source from one to another. Methods: Protein expression of MCT1 and MCT4 was determined in MCF7(control), MDA-MB231, MDA-MB468, and HCC38 cells (TNBC cell lines). IC50s for platinum was calculated by the sulforhodamine B (SRB) assay. The expression of MCT1 and MCT4 responsible for the intracellular influx and efflux was determined by immunohistochemistry in archived tumor tissue from 78 patients with primary TNBC and correlated with tumor size derived from the AJCC TNM classification. MCT1 and MCT4 were also studied in patients with recurrent and metastatic breast cancer. Ethical approval was granted from the Imperial College NHS Healthcare Trust Tissue Bank. Results: MCT1 was highly expressed in HCC38 cells but not at all in MDA-MB231. In contrast, MCT4 was abundantly expressed in MDA-MB231 but minimally in HCC38 cells. These cell lines, MDA-MB231 and HCC38 cells were resistant to platinum. Both MCT1 and MCT4 protein expression levels were significantly increased in T 2, 3 and 4 patients compared to T1 patients, suggesting that bigger and rapidly growing tumor prioritize MCT1/4 – lactate – OXPHOS metabolic pathway compared to the less proliferative small sized-tumor. On the other hand, no correlations were observed between primary/recurrence and node negative/positive in MCT1 and MCT4 expression. Conclusion: Lactate metabolism is upregulated in growing tumors, which may present an opportunity window for targeted therapies directed at the MCT1 and MCT4 receptors. Citation Format: Narumi Harada, Francesco A Mauri, Laura Kenny. Fuel switch from glucose to lactate is dependent on tumor size in triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A81.