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.

Acetyl-CoA carboxylase 1 controls a lipid droplet-peroxisome axis and is a vulnerability of endocrine-resistant ER+ breast cancer / 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; Bachi, Angela; Chiarugi, Paola; Marangoni, Elisabetta; Morandi, Andrea. - In: SCIENCE TRANSLATIONAL MEDICINE. - ISSN 1946-6242. - ELETTRONICO. - 16:(2024), pp. eadf9874.0-eadf9874.0. [10.1126/scitranslmed.adf9874]

Acetyl-CoA carboxylase 1 controls a lipid droplet-peroxisome axis and is a vulnerability of endocrine-resistant ER+ breast cancer

Bacci, Marina;Lorito, Nicla;Smiriglia, Alfredo;Subbiani, Angela;Bonechi, Francesca;Comito, Giuseppina;Benelli, Matteo;Ippolito, Luigi;Giannoni, Elisa;Meattini, Icro;Chiarugi, Paola;Morandi, Andrea
2024

Abstract

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.
2024
16
0
0
Bacci, Marina; Lorito, Nicla; Smiriglia, Alfredo; Subbiani, Angela; Bonechi, Francesca; Comito, Giuseppina; Morriset, Ludivine; El Botty, Rania; Benel...espandi
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1353991
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 1
  • ???jsp.display-item.citation.isi??? 1
social impact