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Neurofibromin Is an Estrogen Receptor-α Transcriptional Co-repressor in Breast Cancer.
Cancer Cell ( IF 48.8 ) Pub Date : 2020-02-25 , DOI: 10.1016/j.ccell.2020.02.003 Ze-Yi Zheng 1 , Meenakshi Anurag 1 , Jonathan T Lei 2 , Jin Cao 3 , Purba Singh 1 , Jianheng Peng 4 , Hilda Kennedy 1 , Nhu-Chau Nguyen 1 , Yue Chen 5 , Philip Lavere 3 , Jing Li 1 , Xin-Hui Du 6 , Burcu Cakar 1 , Wei Song 1 , Beom-Jun Kim 1 , Jiejun Shi 1 , Sinem Seker 1 , Doug W Chan 7 , Guo-Qiang Zhao 8 , Xi Chen 3 , Kimberly C Banks 9 , Richard B Lanman 9 , Maryam Nemati Shafaee 1 , Xiang H-F Zhang 7 , Suhas Vasaikar 1 , Bing Zhang 1 , Susan G Hilsenbeck 1 , Wei Li 1 , Charles E Foulds 10 , Matthew J Ellis 11 , Eric C Chang 7
Cancer Cell ( IF 48.8 ) Pub Date : 2020-02-25 , DOI: 10.1016/j.ccell.2020.02.003 Ze-Yi Zheng 1 , Meenakshi Anurag 1 , Jonathan T Lei 2 , Jin Cao 3 , Purba Singh 1 , Jianheng Peng 4 , Hilda Kennedy 1 , Nhu-Chau Nguyen 1 , Yue Chen 5 , Philip Lavere 3 , Jing Li 1 , Xin-Hui Du 6 , Burcu Cakar 1 , Wei Song 1 , Beom-Jun Kim 1 , Jiejun Shi 1 , Sinem Seker 1 , Doug W Chan 7 , Guo-Qiang Zhao 8 , Xi Chen 3 , Kimberly C Banks 9 , Richard B Lanman 9 , Maryam Nemati Shafaee 1 , Xiang H-F Zhang 7 , Suhas Vasaikar 1 , Bing Zhang 1 , Susan G Hilsenbeck 1 , Wei Li 1 , Charles E Foulds 10 , Matthew J Ellis 11 , Eric C Chang 7
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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-rich motifs that are functionally independent of GAP activity. GAP activity, in turn, does not affect ER binding. Consequently, neurofibromin depletion causes estradiol hypersensitivity and tamoxifen agonism, explaining the poor prognosis associated with neurofibromin loss 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 be reversed upon MEK inhibitor addition, and SERD/MEK inhibitor combinations induce tumor regression. Thus, neurofibromin is a dual repressor for both Ras and ER signaling, and co-targeting may treat neurofibromin-deficient ER+ breast tumors.
中文翻译：
神经纤维蛋白是乳腺癌中的雌激素受体-α 转录共阻遏物。
我们报告说，神经纤维蛋白，一种肿瘤抑制因子和 Ras-GAP（GTPase 激活蛋白），也是一种雌激素受体-α（ER）转录共抑制因子，通过富含亮氨酸/异亮氨酸的基序在功能上独立于 GAP 活性。反过来，GAP 活动不影响 ER 结合。因此，神经纤维蛋白耗竭导致雌二醇超敏反应和他莫昔芬激动，这解释了内分泌治疗治疗的 ER+ 乳腺癌中与神经纤维蛋白丢失相关的不良预后。神经纤维蛋白缺陷的 ER+ 乳腺癌细胞最初保留对选择性 ER 降解剂 (SERD) 的敏感性。然而，Ras 激活确实在获得性 SERD 抗性中起作用，这可以在添加 MEK 抑制剂后逆转，并且 SERD/MEK 抑制剂组合诱导肿瘤消退。因此，
更新日期：2020-03-05
中文翻译：
神经纤维蛋白是乳腺癌中的雌激素受体-α 转录共阻遏物。
我们报告说，神经纤维蛋白，一种肿瘤抑制因子和 Ras-GAP（GTPase 激活蛋白），也是一种雌激素受体-α（ER）转录共抑制因子，通过富含亮氨酸/异亮氨酸的基序在功能上独立于 GAP 活性。反过来，GAP 活动不影响 ER 结合。因此，神经纤维蛋白耗竭导致雌二醇超敏反应和他莫昔芬激动，这解释了内分泌治疗治疗的 ER+ 乳腺癌中与神经纤维蛋白丢失相关的不良预后。神经纤维蛋白缺陷的 ER+ 乳腺癌细胞最初保留对选择性 ER 降解剂 (SERD) 的敏感性。然而，Ras 激活确实在获得性 SERD 抗性中起作用，这可以在添加 MEK 抑制剂后逆转，并且 SERD/MEK 抑制剂组合诱导肿瘤消退。因此，
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