Abstract
IntroductionAldehyde dehydrogenase 1A3 (ALDH1A3) is a cancer stem cell (CSC) marker and in breast cancer it is associated with triple-negative/basal-like subtypes and aggressive disease. Studies on the mechanisms of ALDH1A3 in cancer have primarily focused on gene expression changes induced by the enzyme; however, its effects on metabolism have thus far been unstudied and may reveal novel mechanisms of pathogenesis.ObjectiveDetermine how ALDH1A3 alters the metabolite profile in breast cancer cells and assess potential impacts.MethodTriple-negative MDA-MB-231 tumors and cells with manipulated ALDH1A3 levels were assessed by HPLC–MS metabolomics and metabolite data was integrated with transcriptome data. Mice harboring MDA-MB-231 tumors with or without altered ALDH1A3 expression were treated with γ-aminobutyric acid (GABA) or placebo. Effects on tumor growth, and lungs and brain metastasis were quantified by staining of fixed thin sections and quantitative PCR. Breast cancer patient datasets from TCGA, METABRIC and GEO were used to assess the co-expression of GABA pathway genes with ALDH1A3.ResultsIntegrated metabolomic and transcriptome data identified GABA metabolism as a primary dysregulated pathway in ALDH1A3 expressing breast tumors. Both ALDH1A3 and GABA treatment enhanced metastasis. Patient dataset analyses revealed expression association between ALDH1A3 and GABA pathway genes and corresponding increased risk of metastasis.ConclusionThis study revealed a novel pathway affected by ALDH1A3, GABA metabolism. Like ALDH1A3 expression, GABA treatment promotes metastasis. Given the clinical use of GABA mimics to relieve chemotherapy-induced peripheral nerve pain, further study of the effects of GABA in breast cancer progression is warranted.
Highlights
Aldehyde dehydrogenase 1A3 (ALDH1A3) is a cancer stem cell (CSC) marker and in breast cancer it is associated with triple-negative/basal-like subtypes and aggressive disease
3.1 Metabolomics analysis revealed that gene expression/metabolite network with γ-aminobutyric acid (GABA) degradation is dysregulated by aldehyde dehydrogenase 1A3 (ALDH1A3) expression in MDA‐MB‐231 tumors
MDA-MB-231 cells have limited expression of ALDH1A3, and the overexpression of ALDH1A3 in the triple-negative breast cancer (TNBC) cells has been used to model the effect of high ALDH1A3 levels on the metastasis of TNBCs (Coyle et al, 2017; Marcato et al, 2015; Thomas et al, 2016)
Summary
Aldehyde dehydrogenase 1A3 (ALDH1A3) is a cancer stem cell (CSC) marker and in breast cancer it is associated with triple-negative/basal-like subtypes and aggressive disease. There remains a population of patients with aggressive disease who do not benefit from these targeted therapies as their tumors do not express the necessary hormone receptors (estrogen receptor [ER], progesterone receptor [PR], or epidermal growth factor receptor [HER2]). These triple-negative breast cancer (TNBC) patients have an intrinsically more aggressive disease and worse prognosis which is exacerbated by the lack of effective therapies. A contributing factor for why TNBC is an aggressive disease is the high aldehyde dehydrogenase 1A3 (ALDH1A3) levels present in the subtype, which promotes tumor progression and metastasis. While ALDH1A3 inhibitors are under development, understanding how ALDH1A3 contributes to growth and metastasis could reveal novel avenues for targeting aggressive TNBC and CSCs (Dinavahi et al, 2019)
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