Ebbesen Saya H, Scaltriti Maurizio, Bialucha Carl U, Morse Natasha, Kastenhuber Edward R, Wen Hannah Y, Dow Lukas E, Baselga José, Lowe Scott W
Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):3030-5. doi: 10.1073/pnas.1523693113. Epub 2016 Feb 29.
Loss of the tumor suppressor gene PTEN is implicated in breast cancer progression and resistance to targeted therapies, and is thought to promote tumorigenesis by activating PI3K signaling. In a transgenic model of breast cancer, Pten suppression using a tetracycline-regulatable short hairpin (sh)RNA cooperates with human epidermal growth factor receptor 2 (HER2/neu), leading to aggressive and metastatic disease with elevated signaling through PI3K and, surprisingly, the mitogen-activated protein kinase (MAPK) pathway. Restoring Pten function is sufficient to down-regulate both PI3K and MAPK signaling and triggers dramatic tumor regression. Pharmacologic inhibition of MAPK signaling produces similar effects to Pten restoration, suggesting that the MAPK pathway contributes to the maintenance of advanced breast cancers harboring Pten loss.
肿瘤抑制基因PTEN的缺失与乳腺癌进展及对靶向治疗的耐药性有关，并且被认为通过激活PI3K信号传导促进肿瘤发生。在一个乳腺癌转基因模型中，使用四环素可调控短发夹（sh）RNA抑制Pten与人类表皮生长因子受体2（HER2/neu）协同作用，导致侵袭性和转移性疾病，PI3K信号传导增强，令人惊讶的是，有丝分裂原活化蛋白激酶（MAPK）途径的信号传导也增强。恢复Pten功能足以下调PI3K和MAPK信号传导，并引发显著的肿瘤消退。MAPK信号传导的药理学抑制产生与Pten恢复相似的效果，表明MAPK途径有助于维持存在Pten缺失的晚期乳腺癌。
