Lysine in Combination With Estradiol Promote Dissemination of Estrogen Receptor Positive Breast Cancer via Upregulation of U2AF1 and RPN2 Proteins

Abstract

The majority of estrogen receptor positive (ER+) breast cancer (BC) maintain the ER at metastatic sites. Despite anti-estrogen therapy, almost 30% of ER+ BC patients relapse. Thus, new therapeutic targets for ER+ BC are needed. Amino acids (AAs) may affect the metastatic capacity by affecting inflammatory cells. Essential AAs (EAAs) cannot be produced by human cells and might therefore be targetable as therapeutics. Here we sampled extracellular EAAs in vivo by microdialysis in human BC. Mass spectrometry-based proteomics was used to identify proteins affected after EAA and estradiol (E2) exposure to BC cells. Proteins relevant for patient survival were identified, knocked down in BC cells, and metastatic capability was determined in vivo in the transgenic zebrafish model. We found that lysine was the most utilized EAA in human ER+BC in vivo. In zebrafish, lysine in presence of E2 increased neutrophil-dependent dissemination of ER+ BC cells via upregulation of U2AF1 and RPN2 proteins, which both correlated with poor prognosis of ER+ BC patients in clinical databases. Knockdown of U2AF1 and RPN2 decreased the expression of several cell-adhesion molecules resulting in diminished dissemination. Dietary lysine or its related metabolic pathways may be useful therapeutic targets in ER+ BC.

Supervised discovery of interpretable gene programs from single-cell data

“…5a ). Lysine is an essential amino acid found at lower concentrations in malignant lesions than adjacent normal breast tissue, likely due to the high metabolic demands of the tumor 43 . Among the top 50 marker genes of the lysine factor, Spectra retained 72% of the input gene set, including all key metabolic enzymes; it removed redundant amino acid transporters ( SLC25A21 , SLC38A4 , SLC6A14 , SLC7A3 ); and it retrieved degradation genes ( PYCR2, PYCR3, SLC25A15 ) not found in the input set ( Fig.…”

Comparison of serum metabolomics in women with breast Cancer Prior to Chemotherapy and at 1 year: cardiometabolic implications

“…In an animal model, lysine supplementation was shown to increase the spread of ER + breast cancer cells. Pipecolic acid (a metabolite of lysine) has been implicated in other cancers such as prostate and renal cell carcinoma, but its connection to breast cancer survivorship is currently unknown [ 21 , 22 ]. In addition to perturbations in lysine regulation, we noted downregulated biosynthesis of unsaturated fatty acids: One study in women undergoing treatment for breast cancer with serum samples collected prior to chemotherapy (baseline; n = 50), just after the fourth cycle of chemotherapy (chemo-4; n = 40), and 6 months after beginning chemotherapy (6 M; n = 34) suggested a dysregulation of PUFAs post-chemotherapy with higher serum PUFAs associated with lower inflammation before, during, and after chemotherapy [ 23 ] suggests that n-3 polyunsaturated fatty acid (n-3 PUFA) supplementation during cancer chemotherapy may improve outcomes related to chemotherapy tolerability, [ 24 ].…”

Establishment of a lncRNA-Based Prognostic Gene Signature Associated With Altered Immune Responses in HCC

“…In the KEGG pathway analysis, while 7 of the top 18 pathways affected by AC116025.2 upregulation were metabolism-related, none of the top 14 affected by LNC001134 were ( Figures 6B, D ), even though they both affected bile acid metabolism and fatty acid metabolism in the GSEA enrichment assay ( Figures 6C, F ). Tumor cell metabolism reprograms immune cell infiltration ( 78 , 79 ), so the association of AC116025.2 with alterations in multiple metabolic pathways could suggest how AC116025.2 might modulate T cell exclusion.…”