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

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. [Display omitted] •NF1 is a GAP-independent estrogen receptor transcription co-repressor•Somatic NF1 loss causes tamoxifen/aromatase inhibitor resistance in ER+ breast cancer•A MEK inhibitor plus a SERD is effective in NF1– ER+ PDX and cell line models Zheng et al. find that the Ras-GAP NF1 is also a transcriptional co-repressor of estrogen receptor α (ER). NF1 loss leads to estradiol hypersensitivity and tamoxifen agonism. A selective ER degrader and MEK inhibitor combination induces tumor regression in mouse models of NF1-deficient ER+ breast cancer.