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

Cancer Cell. 2020 Mar 16;37(3):387-402.e7. doi: 10.1016/j.ccell.2020.02.003. Epub 2020 Mar 5.

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.

Keywords: Drosophila; GTPase; NF1; RAS; breast cancer; co-regulator; endocrine therapy; estrogen receptor; neurofibromatosis; yeast.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Co-Repressor Proteins
  • Estrogen Antagonists / pharmacology
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism
  • Female
  • Humans
  • MCF-7 Cells
  • Mice, Nude
  • Mice, SCID
  • Mutation
  • Neurofibromin 1 / chemistry
  • Neurofibromin 1 / genetics*
  • Neurofibromin 1 / metabolism
  • Signal Transduction
  • Tamoxifen / pharmacology
  • Xenograft Model Antitumor Assays
  • ras Proteins / metabolism

Substances

  • Co-Repressor Proteins
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • NF1 protein, human
  • Neurofibromin 1
  • estrogen receptor alpha, human
  • Tamoxifen
  • ras Proteins