Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany; Technical University Munich, 85764 Neuherberg, Germany; Deutsches Zentrum für Diabetesforschung, 85764 Neuherberg, Germany.
Core Facility Tumor Models, German Cancer Research Center (DKFZ) and Medical Faculty Mannheim, Heidelberg University, 69120 Heidelberg, Germany.
Cell Metab. 2017 Dec 5;26(6):842-855.e5. doi: 10.1016/j.cmet.2017.09.018. Epub 2017 Oct 19.
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.
乳腺癌的复发和转移是女性癌症相关死亡的主要原因，但目前仍缺乏有效的治疗方法。在这里，我们将生脂酶乙酰辅酶 A 羧化酶 (ACC) 1 定义为乳腺癌转移的关键因素。在小鼠和人类乳腺癌中，侵袭细胞中的 ACC1 磷酸化增加，作为瘦素和转化生长因子 (TGF) β 信号的交汇点。ACC1 磷酸化由 TGFβ 激活激酶 (TAK) 1 介导，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的上皮-间充质转化和转移诱导是必不可少的。在小鼠中，ACC1 缺陷使原发性肿瘤切除后肿瘤复发恶化，并且在乳腺癌和肺癌患者中，ACC1 磷酸化水平与转移潜能相关。鉴于抗瘦素受体抗体治疗在阻止 ACC1 依赖性肿瘤侵袭方面的有效性，我们的工作定义了转移性乳腺癌治疗中的“代谢中心”方法。
