Prognostic Significance of Amino Acid Transporters in Endometrial Cancer

Background: Identification of high-risk patients with endometrial cancer (EC) remains challenging despite advances in molecular profiling. Methods: We comprehensively analyzed the RNA expression of 18 amino acid transporters (AATs) in 373 EC samples from The Cancer Genome Atlas (TCGA). Results: Our clustering analysis based on AAT expression identified a patient group with a significantly worse prognosis. Sideroflexin family (SFXN1, SFXN5), glutamine (SLC38A1, SLC38A3), glycine (SLC6A9) transporters, and the heavy-chain subunit of heteromeric AATs (SLC3A2) were elevated in poorly differentiated tumors. In contrast, the transporter of small neutral amino acids (SLC1A4) and proline/imino-acid transporter (SLC6A20) were enriched in lower-grade disease. SFXN1 and SLC38A1 were also higher in advanced (III/IV) FIGO stages. AAT expression differed across molecular subtypes, with SFXN5, SLC38A1, SLC38A3, and SLC3A2 associated with the copy-number-high profile. In survival analysis, we demonstrated that SLC38A3, SFXN4, and SLC3A2 were associated with shorter disease-free survival, and SLC38A1, SLC38A3, and SFXN1 with worse overall survival, whereas SLC1A4, SLC6A20, and the taurine transporter (SLC6A6) were related to favorable outcomes. Conclusions: These findings highlight AAT expression as a potential marker of EC aggressiveness and prognosis and suggest that integrating metabolic features with molecular classification may improve risk stratification and identify potential therapeutic targets.