ALDH1 subtype-specific inhibitor targets key cell populations in triple negative breast cancer

Breast cancer exhibits significant heterogeneity, making the identification of molecular targets critical for the development of effective therapies. In this study, we investigate the expression patterns of the ALDH1A enzyme subfamily- ALDH1A1, ALDH1A2, and ALDH1A3- across diverse molecular subtypes and the tumor microenvironment, with a particular focus on triple-negative breast cancer (TNBC). Notably, ALDH1A3 is predominantly expressed in basal-like tumors and is significantly enriched in epithelial cells. In contrast, ALDH1A1 is uniquely expressed in myeloid cells and cancer-associated fibroblasts (CAFs). This dual expression pattern underscores the critical roles of ALDH1A3 and ALDH1A1 within the tumor microenvironment. We also evaluated the activity of novel ALDH1A inhibitors, specifically ABD0171, which demonstrated selective cytotoxicity in ALDH1A3-expressing basal-like cells and induced apoptosis through activation of the death receptor pathway. Both ABD0171 and its precursor, DIMATE, exhibited potent anti-metastatic effects, likely via inhibition of IL6/JAK/STAT3 signalling, and significantly inhibited tumor growth in preclinical TNBC models. These findings underscore the therapeutic potential of targeting ALDH1A isoforms, particularly ALDH1A3, in aggressive breast cancer subtypes and highlight the importance of considering tumor heterogeneity in the development of targeted therapies.