Amino acid metabolism in breast cancer as a driver of disease and therapeutic target

The review introduces the molecular subtypes of breast cancer and outlines how altered amino acid metabolism supports tumor growth. It explores key amino acid pathways—including glutamine, serine, glycine, aspartate, arginine, and tryptophan—and their roles in energy production, redox homeostasis, biosynthesis, and immune modulation. It also highlights the involvement of specific transporters and enzymes, and discusses emerging clinical applications, such as metabolic imaging and personalized therapies based on metabolic dependencies.

Key points of the review include:

1. Glutamine metabolism: Glutamine serves as both nitrogen and carbon sources for cancer cells. Enzymes like GLS1 and GLS2 are differentially expressed across subtypes. TNBC shows high glutamine dependency, making glutaminase a promising therapeutic target.
2. Serine and glycine metabolism: Serine is essential for nucleotide synthesis and redox balance. Overexpression of PHGDH and PSAT1 is common in aggressive tumors like TNBC and HER2+, suggesting vulnerability to serine biosynthesis inhibition.
3. Aspartate and asparagine metabolism: Aspartate is vital for cell proliferation and nucleotide synthesis. High ASNS expression supports survival under stress. Aspartate also shows promise as a diagnostic biomarker for early-stage breast cancer.
4. Arginine metabolism: breast tumors suppress ASS1, making them reliant on external arginine. Arginine deprivation strategies, like ADI-PEG20 treatment, are effective especially in TNBC. Arginine metabolism also influences redox and epigenetic regulation.
5. Tryptophan metabolism: IDO1 and TDO2 convert tryptophan into kynurenine, promoting immune escape. This pathway is especially active in TNBC. Inhibiting IDO1/TDO2 can reverse immunosuppression and reduce metastasis.

Amino acid metabolism is fundamentally linked to breast cancer subtype biology and therapeutic resistance. Different subtypes show distinct metabolic dependencies that can be exploited for targeted therapy. Transporters and metabolic enzymes represent promising drug targets, while imaging techniques and personalized strategies may enhance diagnostic accuracy and treatment effectiveness. Understanding and manipulating these metabolic networks could pave the way for more effective, precision-based interventions in breast cancer care. The work entitled " Amino Acid Metabolism in Breast Cancer: Pathogenic Drivers and Therapeutic Opportunities " was published on Protein & Cell (published on Feb. 20, 2025).