小柯机器人

美国贝勒医学院丹•邓肯综合癌症中心Eric C. Chang研究组的最新研究发现在乳腺癌中神经纤维瘤蛋白是雌激素受体-α的转录共遏因子。该研究于2020年3月5日在线发表在《癌细胞》杂志上。

研究人员发现正如Ras-GAP（GTPase激活蛋白），肿瘤抑制因子神经纤维瘤蛋白也是依赖亮氨酸/异亮氨酸丰富结构域的雌激素受体-α（ER）的转录共遏物，该功能是发挥不依赖GAP活性。相反，GAP活性对ER结合没有影响。因此，神经纤维瘤蛋白缺失引起雌二醇超敏和他莫昔芬的激活，这解释了内分泌疗法治疗的ER ⁺乳腺癌中与神经纤维瘤蛋白缺失相关的不良预后。

缺乏神经纤维瘤蛋白的ER ⁺乳腺癌细胞最初对选择性ER降解因子（SERD）保持敏感，但是Ras激活确实在获得性SERD耐药中起作用，在使用MEK抑制剂后得到逆转，并且SERD / MEK抑制剂组合可引起肿瘤减小。因此，神经纤维瘤蛋白可同时抑制Ras和ER信号传导，并且共同靶向可治疗神经纤维瘤蛋白缺乏的ER ⁺乳腺肿瘤。

附：英文原文

Title: Neurofibromin Is an Estrogen Receptor-α Transcriptional Co-repressor in Breast Cancer

Author: Ze-Yi Zheng, Meenakshi Anurag, Jonathan T. Lei, Jin Cao, Purba Singh, Jianheng Peng, Hilda Kennedy, Nhu-Chau Nguyen, Yue Chen, Philip Lavere, Jing Li, Xin-Hui Du, Burcu Cakar, Wei Song, Beom-Jun Kim, Jiejun Shi, Sinem Seker, Doug W. Chan, Guo-Qiang Zhao, Xi Chen, Kimberly C. Banks, Richard B. Lanman, Maryam Nemati Shafaee, Xiang H.-F. Zhang, Suhas Vasaikar, Bing Zhang, Susan G. Hilsenbeck, Wei Li, Charles E. Foulds, Matthew J. Ellis, Eric C. Chang

Issue&Volume: 2020-03-05

Abstract: We report that neurofibromin, a tumor suppressor and Ras-GAP (GTPase-activating protein),is also an estrogen receptor-α (ER) transcriptional co-repressor through leucine/isoleucine-richmotifs that are functionally independent of GAP activity. GAP activity, in turn, doesnot affect ER binding. Consequently, neurofibromin depletion causes estradiol hypersensitivityand tamoxifen agonism, explaining the poor prognosis associated with neurofibrominloss in endocrine therapy-treated ER+ breast cancer. Neurofibromin-deficient ER+ breast cancer cells initially retain sensitivity to selective ER degraders (SERDs).However, Ras activation does play a role in acquired SERD resistance, which can bereversed upon MEK inhibitor addition, and SERD/MEK inhibitor combinations induce tumorregression. Thus, neurofibromin is a dual repressor for both Ras and ER signaling,and co-targeting may treat neurofibromin-deficient ER+ breast tumors.

DOI: 10.1016/j.ccell.2020.02.003

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30092-1

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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