Targeting MUC1-Mediated Tumor-Stromal Metabolic Interaction in Triple-Negative Breast Cancer
Annual rept. 15 Sep 2013-14 Sep 2014
NEBRASKA UNIV AT OMAHA
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Mucin1 MUC1, a glycoprotein is aberrantly overexpressed in TNBC and facilitates growth and metastasis of triple negative breast cancer TNBC cells. This occurrence can be partially attributed to MUC1 interaction with hypoxia-inducible factor alpha HIF1 , a key regulator of glycolysis. We previously observed that ectopic overexpression of MUC1 increased glucose uptake, lactate secretion and enhanced the expression of glycolytic enzymes. Therefore we hypothesized that MUC1 stabilizes HIF1 to facilitate metabolic reprogramming. In the present study MUC1-overexpressing cells MDA-MB-231.MUC1 demonstrated that MUC1 alters expression of several metabolic genes. Metabolic gene alterations was also observed in MUC1 compared to Neo after stimulating cells with EGF, which induces nuclear localization and transcriptional activation of the cytoplasmic tail of MUC1. Additionally, MUC1 enhanced glutamine uptake that was increaseddecreased under hypoxic conditions and increased nucleotide biosynthesis to support cell growth. Lastly, MUC1 increaseddecreased oxygen consumption rate OCR and extracellular acidification rate ECAR, indicative of cells utilizing glycolysis andor oxidative phosphorylation to meet energy requirements. Thus our results support the notion that MUC1 serves as a metabolic regulator in TNBC, facilitating metabolic reprogramming that influences growth of TNBC.
- Anatomy and Physiology
- Medicine and Medical Research