Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Rosalind & Morris Goodman Cancer Centre, McGill University, Montreal, QC H3A 1A3, Canada.
Center for Comparative Medicine, University of California, Davis, Davis, CA 95616, USA.
Cell Rep. 2020 Apr 28;31(4):107571. doi: 10.1016/j.celrep.2020.107571.
Mechanistic target of rapamycin complex 1 (mTORC1) is a master modulator of cellular growth, and its aberrant regulation is recurrently documented within breast cancer. While the small GTPase Rheb1 is the canonical activator of mTORC1, Rheb1-independent mechanisms of mTORC1 activation have also been reported but have not been fully understood. Employing multiple transgenic mouse models of breast cancer, we report that ablation of Rheb1 significantly impedes mammary tumorigenesis. In the absence of Rheb1, a block in tumor initiation can be overcome by multiple independent mutations in Mtor to allow Rheb1-independent reactivation of mTORC1. We further demonstrate that the mTOR kinase is indispensable for tumor initiation as the genetic ablation of mTOR abolishes mammary tumorigenesis. Collectively, our findings demonstrate that mTORC1 activation is indispensable for mammary tumor initiation and that tumors acquire alternative mechanisms of mTORC1 activation.
雷帕霉素靶蛋白复合物 1（mTORC1）是细胞生长的主要调节剂，其在乳腺癌中的异常调节经常被记录。虽然小分子 GTPase Rheb1 是 mTORC1 的经典激活剂，但也已经报道了 Rheb1 非依赖性的 mTORC1 激活机制，但尚未完全理解。我们使用多种乳腺癌转基因小鼠模型报告称，Rheb1 的缺失显著阻碍了乳腺肿瘤的发生。在缺乏 Rheb1 的情况下，通过 Mtor 中的多个独立突变可以克服肿瘤起始的阻断，从而允许 Rheb1 非依赖性的 mTORC1 再激活。我们进一步证明，mTOR 激酶对于肿瘤起始是必不可少的，因为 mTOR 的基因缺失会消除乳腺肿瘤发生。总之，我们的研究结果表明，mTORC1 的激活对于乳腺肿瘤起始是必不可少的，并且肿瘤会获得 mTORC1 激活的替代机制。
