Neurofibromin is an Estrogen Receptor alpha Transcriptional Co-repressor in Breast cancer

We report that neurofibromin, a tumor suppressor and Ras-GAP (GTPase Activating Protein), is also an estrogen receptor-alpha (ER) transcriptional co-repressor through leucine/isoleucine-rich motifs that are functionally independent of GAP activity. GAP activity, in turn, does not impact 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 estrogen receptor 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. RNA-seq of doxycycline inducible knockdown of NF1 in hormone-deprived MCF7 cells -/+ E2, and RNA-seq of NF1 wildtype and mutant CRISPR knock-in hormone-deprived MCF7 cells.