Breast tumor recurrence and metastasis represent the main causes of cancer-related death in women, and treatments are still lacking. Here, we define the lipogenic enzyme acetyl-CoA carboxylase (ACC) 1 as a key player in breast cancer metastasis. ACC1 phosphorylation was increased in invading cells both in murine and human breast cancer, serving as a point of convergence for leptin and transforming growth factor (TGF) β signaling. ACC1 phosphorylation was mediated by TGFβ-activated kinase (TAK) 1, and ACC1 inhibition was indispensable for the elevation of cellular acetyl-CoA, the subsequent increase in Smad2 transcription factor acetylation and activation, and ultimately epithelial-mesenchymal transition and metastasis induction. ACC1 deficiency worsened tumor recurrence upon primary tumor resection in mice, and ACC1 phosphorylation levels correlated with metastatic potential in breast and lung cancer patients. Given the demonstrated effectiveness of anti-leptin receptor antibody treatment in halting ACC1-dependent tumor invasiveness, our work defines a "metabolocentric" approach in metastatic breast cancer therapy.

中文翻译：

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乙酰辅酶A羧化酶1依赖性蛋白乙酰化控制乳腺癌的转移和复发。

乳腺癌的复发和转移是女性癌症相关死亡的主要原因，目前仍缺乏治疗方法。在这里，我们将脂肪酶乙酰辅酶A羧化酶（ACC）1定义为乳腺癌转移的关键参与者。在鼠和人乳腺癌的侵袭细胞中，ACC1磷酸化均增加，是瘦素和转化生长因子（TGF）β信号转导的汇合点。ACC1磷酸化是由TGFβ活化激酶（TAK）1介导的，而ACC1抑制对于细胞乙酰辅酶A的升高，随后Smad2转录因子乙酰化和激活的增加以及最终上皮-间质转化和转移诱导是必不可少的。ACC1缺乏使小鼠原发肿瘤切除后的肿瘤复发恶化，和ACC1磷酸化水平与乳腺癌和肺癌患者的转移潜能相关。鉴于抗瘦素受体抗体治疗在停止ACC1依赖性肿瘤浸润方面已显示出有效的功效，我们的工作为转移性乳腺癌治疗定义了“以代谢为中心”的方法。