Targeting MUC1-Mediated Tumor-Stromal Metabolic Interactions in Triple-Negative Breast Cancer

Abstract

Abstract : 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 alpha), 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 alpha to facilitate metabolic reprogramming. In the present study we examined the effect of MUC1 expression on cancer cell metabolism of TNBC cell lines. MUC1 was ectopically overexpressed in the MDA-MB231 cell line and stably knocked down in the MDA-MB468 and BT-20 cell lines. Results indicate that MUC1 expression altered the expression of several metabolic genes. Furthermore, untargeted global metabolomic profiling identified metabolite alterations in which MUC1 expression modulates cancer cell metabolism to facilitate growth properties of TNBC cells. Thus our results support the notion that MUC1 serves as a metabolic regulator in TNBC, facilitating metabolic reprogramming that influences growth of TNBC.