Metabolite profiling reveals a connection between aldehyde dehydrogenase 1A3 and GABA metabolism in breast cancer metastasis

Abstract

Introduction 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. 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. Objective Determine how ALDH1A3 alters the metabolite profile in breast cancer cells and assess potential impacts. Method Triple-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. Results Integrated 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. Conclusion This 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.

Breast cancer and neurotransmitters: emerging insights on mechanisms and therapeutic directions

“…Combination with neoadjuvant chemotherapy is also being Fig. 2 Neurotransmitter signaling pathways in breast cancer metastasis [8,45,55,61,93,95,[97][98][99][100]119]. Neurotransmitters such as acetylcholine (Ach), GABA, serotonin (5 HT), norepinephrine (NE), neuropeptide Y (NPY), and neurotensin (NTS) affect cancer progression through multiple signaling pathways.…”

“…Both Neman et al and Dahn et al have found that activation of GABA A receptors increase brain metastases in breast cancer patients. The receptor could therefore represent a promising therapeutic target [ 94 , 95 ].…”

“…Mimics of GABA, an inhibitory neurotransmitter, are frequently used to reduce peripheral nerve pain caused by chemotherapy. However, there is concern that GABA treatment could increase breast cancer metastasis [ 95 ]. Improved understanding will help ascertain if there are any adverse impacts from existing medication use.…”

The tumor-nerve circuit in breast cancer

“…Mechanistically, GABRP silencing decreased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) [33]. Furthermore, GABA enhances the function of aldehyde dehydrogenase (ALDH)1A3, a cancer stem cell (CSC) marker in TNBC [34]. In mice harboring MDA-MB-231 tumors overexpressing ALDH1A3, GABA treatment increased breast cancer metastasis [34].…”

Tumor microenvironment and exosomes in brain metastasis: Molecular mechanisms and clinical application

“…This may induce resistance of tumor cells to certain antimetabolite chemotherapy drugs such as D-2-deoxyglucose (121). Chen et al (122) found that breast cancer cells that metastasize to the brain have greater tolerance to low sugar levels than their parent cells; they also express more glutamate dehydrogenase and a-ketoacid dehydrogenase to use the glutamic acid and branched-chain amino acids available in the environment.…”