| Literature DB >> 32142667 |
Ze-Yi Zheng1, Meenakshi Anurag1, Jonathan T Lei2, Jin Cao3, Purba Singh1, Jianheng Peng4, Hilda Kennedy1, Nhu-Chau Nguyen1, Yue Chen5, Philip Lavere3, Jing Li1, Xin-Hui Du6, Burcu Cakar1, Wei Song1, Beom-Jun Kim1, Jiejun Shi1, Sinem Seker1, Doug W Chan7, Guo-Qiang Zhao8, Xi Chen3, Kimberly C Banks9, Richard B Lanman9, Maryam Nemati Shafaee1, Xiang H-F Zhang7, Suhas Vasaikar1, Bing Zhang1, Susan G Hilsenbeck1, Wei Li1, Charles E Foulds10, Matthew J Ellis11, Eric C Chang12.
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-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.Entities:
Keywords: Drosophila; GTPase; NF1; RAS; breast cancer; co-regulator; endocrine therapy; estrogen receptor; neurofibromatosis; yeast
Mesh：
Substances：
Year: 2020 PMID： 32142667 PMCID： PMC7286719 DOI： 10.1016/j.ccell.2020.02.003
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743