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.
Highlights
Amino acids (AAs) participate in all aspects of the pathophysiological processes that occur in tissues and organs [1]
Protein biosynthesis requires the local availability of AAs in the extracellular microenvironment, which can act as Lysine in Breast Cancer Dissemination signaling molecules that regulate the expression and activity of metastasis-related proteins, such as epithelial-to-mesenchymal transition proteins, matrix metalloproteinases, and focal adhesion kinase phosphorylation [5,6,7,8]
We found that consumption of five Essential AAs (EAAs) was increased in human ER+ breast cancer (BC); the levels were lower in BC than in normal breast tissue, with lysine displaying the most pronounced change
Summary
Amino acids (AAs) participate in all aspects of the pathophysiological processes that occur in tissues and organs [1]. One hallmark of cancer is an increased demand for proteinogenic AAs due to extensive proliferation and metabolic reprogramming [2]. The metastatic capacity of cancer cells might depend on the redirection of AA use [3]. The metabolic reprogramming of cancer cells is coupled to inflammation in the tumor microenvironment, leading to increased immune cell infiltration, which further enhances the metastatic capacity of cancer cells [4]. AAs in the tissue microenvironment play an important role in controlling the progression of cancer. EAAs might be useful as potential targets in cancer therapies. Promising results in experimental cancer models have shown that dietary restriction of EAAs can reduce tumor growth and metastasis [8, 10, 11]
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