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.

中文翻译：

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乙酰辅酶A羧化酶1控制脂滴-过氧化物酶体轴，是内分泌抵抗性ER +乳腺癌的脆弱性

靶向芳香酶剥夺 ER+雌激素的乳腺癌是治疗这些肿瘤的有效方法。然而，耐药性是一个未满足的临床需求。长期雌激素剥夺 (LTED) ER 的脂质组学分析+乳腺癌细胞是芳香酶抑制剂耐药性的模型，显示细胞内脂质储存增强。功能代谢分析表明，脂滴与过氧化物酶体（我们证明它们在 LTED 细胞中富集且活跃）控制氧化还原稳态并赋予耐药肿瘤的代谢适应性。这种重编程是由乙酰辅酶 A 羧化酶 1 (ACC1) 控制的，其目标选择性地损害 LTED 存活。然而，添加支链和超长链脂肪酸会恢复 ACC1 抑制，这是一个由过氧化物酶体功能和氧化还原稳态介导的过程。这些发现的治疗相关性在芳香酶抑制剂治疗的患者来源样本中得到了验证。最后，靶向 ACC1 减少了耐药患者来源的异种移植物的肿瘤生长，从而确定了一个可靶向的中枢来对抗 ER 中雌激素独立性的获得+乳腺癌。