Comparative Analysis of Breast Cancer Metabolomes Highlights Fascin's Central Role in Regulating Key Pathways Related to Disease Progression.

Omics technologies provide useful tools for the identification of novel biomarkers in many diseases, including breast cancer, which is the most diagnosed cancer in women worldwide. We and others have reported a central role for the actin-bundling protein (fascin) in regulating breast cancer disease progression at different levels. However, whether fascin expression promotes metabolic molecules that could predict disease progression has not been fully elucidated. Here, fascin expression was manipulated via knockdown (fascin KD+NORF ) and rescue (fascin KD+FORF ) in the naturally fascin-positive (fascin pos+NORF ) MDA-MB-231 breast cancer cells. Whether fascin dysregulates metabolic profiles that are associated with disease progression was assessed using untargeted metabolomics analyses via liquid chromatography-mass spectrometry. Overall, 12,226 metabolic features were detected in the tested cell pellets. Fascin pos+NORF cell pellets showed 2510 and 3804 significantly dysregulated metabolites compared to their fascin KD+NORF counterparts. Fascin rescue (fascin KD+FORF ) revealed 2710 significantly dysregulated cellular metabolites compared to fascin KD+NORF counterparts. A total of 101 overlapped cellular metabolites between fascin KD+FORF and fascin pos+NORF were significantly dysregulated in the fascin KD+NORF cells. Analysis of the significantly dysregulated metabolites by fascin expression revealed their involvement in the metabolism of sphingolipid, phenylalanine, tyrosine, and tryptophan biosynthesis, and pantothenate and CoA biosynthesis, which are critical pathways for breast cancer progression. Our findings of fascin-mediated alteration of metabolic pathways could be used as putative poor prognostic biomarkers and highlight other underlying mechanisms of fascin contribution to breast cancer progression.