Inter- and intra-tumoral ALDH1 heterogeneity in breast cancer identifies therapeutic opportunities for ALDH1A-specific inhibitors
Basal-like breast cancer is an aggressive subtype with limited therapeutic options. Here, transcriptomic analysis of public datasets suggested distinct subtype- and cell-specific expression patterns of ALDH1A isoforms in breast tumors, with ALDH1A3 predominantly expressed in the epithelial cells of...
| Autores: | , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:321909 |
| Acceso en línea: | https://ddd.uab.cat/record/321909 https://dx.doi.org/urn:doi:10.1016/j.chembiol.2025.09.003 |
| Access Level: | acceso embargado |
| Palabra clave: | Bulk and single-cell transcriptomic analysis Prognostic biomarker Chemoresistance Isoform-specific inhibition TNBC Triple-negative breast cancer Breast cancer ALDH1A3 ALDH1A2 ALDH Aldehyde dehydrogenase |
| Sumario: | Basal-like breast cancer is an aggressive subtype with limited therapeutic options. Here, transcriptomic analysis of public datasets suggested distinct subtype- and cell-specific expression patterns of ALDH1A isoforms in breast tumors, with ALDH1A3 predominantly expressed in the epithelial cells of basal-like tumors, whereas ALDH1A2 and ALDH1A1 were enriched in stromal and immune-associated subpopulations. High expression of ALDH1A3 and ALDH1A2, but not ALDH1A1, is associated with poor prognosis in high-grade, lymph-node-positive tumors. To evaluate therapeutic targeting, we developed ABD0171, an irreversible, selective ALDH1A3 inhibitor with additional ALDH1A1 activity. ABD0171 disrupted key oncogenic pathways, including IL6/JAK/STAT3, tPA, and Src/FAK, resulting in robust antitumor and antimetastatic effects in vitro and in vivo, with a favorable safety profile. These findings establish ALDH1A3 as a therapeutic target in breast cancers with epithelial-basal traits and validate ABD0171 as a promising clinical candidate to address current treatment challenges. |
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