Abstract 3370: Natural compound targeting metabolism: A new insight for the treatment of triple negative breast cancer

Abstract

Abstract Background: Triple-negative breast cancer (TNBC) is a highly diverse group associated with an aggressive phenotype, characterized by early relapse and chemotherapy as the only treatment option. Thus, there is an urgent need to identify alternative strategies for the treatment of TNBC. Use of aerobic glycolysis is important marker of cancer cells and thus monitoring and targeting metabolism in cancer cells is an expanding area of research. Lactate dehydrogenase (LDH) A and B are important enzymes in the metabolic pathway. Traditionally, LDH-A expression has been used to measure the glycolytic capacity of cancer cells however, more recently LDH-B has also been identified as an important biomarker of metabolism. LDH-A is over-expressed in breast cancer, while presence of LDH-B in tumors is contradictory. Higher expression of LDH-B has been reported in normal tissues, with lower expression also noted in breast and prostate tumors. Thus, clarification of the role of LDH-A and LDH-B in cancer metabolism is important in identifying potential targets for TNBC treatment. NF-κB plays an important role in modulating cancer metabolism through regulating the balance between glycolysis and mitochondrial respiration and is over-expressed in TNBCs. Thus, the focus of the present study is to determine the effect of an NF-KB inhibitor in altering cellular metabolism of aggressive breast cancer cells. Experimental Design: We measured the metabolic capacity of several breast cancer cell lines via measurement of mitochondrial membrane potential, ATP level and expression of LDH-A and LDH-B. We then evaluated the ability of the NF-kB inhibitor, panepoxydone (PP), to alter these markers of metabolism. Results: MCF-7 and MDA-MB-231 cells showed dose-dependent decreases in mitochondrial membrane potential, in the form of increased mitochondrial damage, along with decreased ATP levels, when treated with the NF-kB inhibitor, PP. Immunoblotting of LDH-A and LDH-B expression in MCF-7 and MDA-MB-231 cells showed high expression of LDH-A in both cell lines, while MDA-MB-231 cells had a higher level of LDH-A compared to LDH-B, MCF-7 cells had no LDH-B. When these cells were treated with PP, LDH-A levels was reduced in both cancer cell lines (3.5 -4 fold). Interestingly, elevated level of LDH-B was noticed in MDA-MB-231 cells (2 fold). We used Human mammary epithelial cells (HMEC) to check the basal level of LDH-A and LDH-B and almost similar level was observed. Furthermore, this increase in LDH-B was associated with decreased aggressiveness, as noted by decreased invasion and migration. Conclusion: All together this data highlights the role of targeting NF-kB in altering glycolysis through modulation of the membrane potential, ATP level and LDH-A and LDH-B levels. Additionally, it appears that simultaneous measurement, of both LDH-A and LDH-B, may be a more accurate predictor of the metabolic capacity of cancer cells and thus a reflection of their aggressiveness. Citation Format: Ritu Arora, David Schmitt, Steve McClellan, Ming Tan, Windy Dean-Colomb. Natural compound targeting metabolism: A new insight for the treatment of triple negative breast cancer. [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 3370. doi:10.1158/1538-7445.AM2014-3370