| Autor: |
Bacci, Marina, Lorito, Nicla, Smiriglia, Alfredo, Subbiani, Angela, Bonechi, Francesca, Comito, Giuseppina, Morriset, Ludivine, El Botty, Rania, Benelli, Matteo, López-Velazco, Joanna I., Caffarel, Maria M., Urruticoechea, Ander, Sflomos, George, Malorni, Luca, Corsini, Michela, Ippolito, Luigi, Giannoni, Elisa, Meattini, Icro, Matafora, Vittoria, Havas, Kristina |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 2/28/2024, Vol. 16 Issue 736, p1-14, 14p |
| Abstrakt: |
Targeting aromatase deprives ER+ breast cancers of estrogens and is an effective therapeutic approach for these tumors. However, drug resistance is an unmet clinical need. Lipidomic analysis of long-term estrogen-deprived (LTED) ER+ breast cancer cells, a model of aromatase inhibitor resistance, revealed enhanced intracellular lipid storage. Functional metabolic analysis showed that lipid droplets together with peroxisomes, which we showed to be enriched and active in the LTED cells, controlled redox homeostasis and conferred metabolic adaptability to the resistant tumors. This reprogramming was controlled by acetyl-CoA-carboxylase-1 (ACC1), whose targeting selectively impaired LTED survival. However, the addition of branched- and very long–chain fatty acids reverted ACC1 inhibition, a process that was mediated by peroxisome function and redox homeostasis. The therapeutic relevance of these findings was validated in aromatase inhibitor–treated patient-derived samples. Last, targeting ACC1 reduced tumor growth of resistant patient-derived xenografts, thus identifying a targetable hub to combat the acquisition of estrogen independence in ER+ breast cancers. Editor's summary: Aromatase inhibitors prevent estrogen production and can be effective against ER+ breast cancer, but subsequent tumor metabolic adaptation often thwarts treatment efficacy. Bacci et al. report that acetyl-CoA-carboxylase-1 (ACC1) promotes lipid mobilization in estrogen-deprived breast cancer cells, leading to anti-estrogen therapy resistance. Pharmacologically targeting ACC1 in patient-derived, treatment-resistant xenograft models reduced tumor growth and increased mouse survival. This work indicates that targeting ACC1 may be an avenue to resensitize ER+ breast cancer to endocrine-based therapies. —Catherine Charneski [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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