Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
Cancer Res. 2018 Sep 1;78(17):4826-4838. doi: 10.1158/0008-5472.CAN-17-3696. Epub 2018 Jun 21.
The ShcA adaptor protein transduces oncogenic signals downstream of receptor tyrosine kinases. We show here that breast tumors engage the ShcA pathway to increase their metabolism. ShcA signaling enhanced glucose catabolism through glycolysis and oxidative phosphorylation, rendering breast cancer cells critically dependent on glucose. ShcA signaling simultaneously increased the metabolic rate and flexibility of breast cancer cells by inducing the PGC-1α transcriptional coactivator, a central regulator of mitochondrial metabolism. Breast tumors that engaged ShcA signaling were critically dependent on PGC-1α to support their increased metabolic rate. PGC-1α deletion drastically delayed breast tumor onset in an orthotopic mouse model, highlighting a key role for PGC-1α in tumor initiation. Conversely, reduced ShcA signaling impaired both the metabolic rate and flexibility of breast cancer cells, rendering them reliant on mitochondrial oxidative phosphorylation. This metabolic reprogramming exposed a targetable metabolic vulnerability, leading to a sensitization of breast tumors to inhibitors of mitochondrial complex I (biguanides). Genetic inhibition of ShcA signaling in the Polyoma virus middle T (MT) breast cancer mouse model sensitized mammary tumors to biguanides during the earliest stages of breast cancer progression. Tumor initiation and growth were selectively and severely impaired in MT/ShcA-deficient animals. These data demonstrate that metabolic reprogramming is a key component of ShcA signaling and serves an unappreciated yet vital role during breast cancer initiation and progression. These data further unravel a novel interplay between ShcA and PGC-1α in the coordination of metabolic reprogramming and demonstrate the sensitivity of breast tumors to drugs targeting oxidative phosphorylation. This study uncovers a previously unrecognized mechanism that links aberrant RTK signaling with metabolic perturbations in breast cancer and exposes metabolic vulnerabilities that can be targeted by inhibitors of oxidative phosphorylation. .
ShcA 衔接蛋白将受体酪氨酸激酶的致癌信号转导至下游。我们在此表明，乳腺癌通过 ShcA 信号通路增加其代谢。ShcA 信号通过糖酵解和氧化磷酸化增强葡萄糖分解代谢，使乳腺癌细胞严重依赖葡萄糖。ShcA 信号通过诱导 PGC-1α 转录共激活因子同时增加乳腺癌细胞的代谢率和灵活性，PGC-1α 是线粒体代谢的中央调节剂。参与 ShcA 信号的乳腺癌肿瘤严重依赖 PGC-1α 来支持其增加的代谢率。PGC-1α 缺失在原位小鼠模型中极大地延迟了乳腺癌的发生，突出了 PGC-1α 在肿瘤起始中的关键作用。相反，降低 ShcA 信号会损害乳腺癌细胞的代谢率和灵活性，使它们依赖于线粒体氧化磷酸化。这种代谢重编程暴露了可靶向的代谢脆弱性，导致乳腺癌对线粒体复合物 I（双胍类）抑制剂的敏感性增加。ShcA 信号的基因抑制在 Polyoma 病毒中间 T（MT）乳腺癌小鼠模型中使乳腺癌对双胍类药物在乳腺癌进展的最早阶段敏感。MT/ShcA 缺陷动物的肿瘤起始和生长受到选择性和严重损害。这些数据表明，代谢重编程是 ShcA 信号的关键组成部分，在乳腺癌起始和进展过程中发挥了未被充分认识但至关重要的作用。这些数据进一步揭示了 ShcA 和 PGC-1α 之间在协调代谢重编程中的新相互作用，并证明了乳腺癌对靶向氧化磷酸化的药物的敏感性。这项研究揭示了一种以前未被识别的机制，将异常的 RTK 信号与乳腺癌中的代谢紊乱联系起来，并暴露了可以通过氧化磷酸化抑制剂靶向的代谢脆弱性。
