Clinical implications of 10-formyltetrahydrofolate dehydrogenase expression in hormone receptor-positive breast cancer

Objective: ALDH1L1, a key enzyme in folate metabolism, has been implicated in various cancers, but the clinical significance of its expression in breast cancer remains unclear. Methods: We analyzed three cohorts from Seoul National University Hospital: (i) 41 non-matched patient samples (23 samples from normal mammary tissues and 18 samples from invasive carcinoma); (ii) 44 paired normal and invasive mammary carcinoma patient tissues; (iii) tissue microarray of 1,001 invasive ductal carcinoma patients. ALDH1L1 immunostaining was performed on 1,086 cases (combined samples from the three cohorts) using tissue microarrays or whole section slides with positive cytoplasmic and membranous reactivity. Clinical (tumor size, grade, lymphatic invasion, and lymph node metastasis) data were collected from patient records. Results: ALDH1L1 expression was higher in non-tumor tissues than cancer tissues (p=0.0014 and p=0.0282 for two datasets), and inversely correlated with increased tumor size, advanced stage, and lymphatic spread. Higher ALDH1L1 expression is associated with smaller tumor size, lower pT stage in luminal A and HER2+ subtypes, and lower nuclear grade in triple-negative breast cancer. ALDH1L1 expression was associated with improved overall and disease-free survival, particularly in hormone receptor-positive subtypes (p=0.0049 and p=0.0441). These findings were confirmed by METABRIC database analysis. In agreement with the association between ALDH1L1 expression and tumor aggressiveness, proliferation/clonogenic assays showed strong cytotoxic effects of lentivirus-delivered ALDH1L1 in MCF7 and T47D luminal breast cancer cells. Conclusion: Reduced ALDH1L1 expression is associated with aggressive clinicopathologic features and poorer survival in breast cancer, with a particularly evident and clinically relevant prognostic impact in the luminal A subtype. These findings highlight ALDH1L1 as a subtype-specific favorable biomarker and a potential therapeutic target in hormone receptor-positive breast cancer.