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  • Neurofibromin Is an Estrogen Receptor-α Transcriptional Co-repressor in Breast Cancer.

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

Cancer cell (2020-03-07)
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
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.

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