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.
Ze-Yi Zheng  1 ,  Meenakshi Anurag  1 ,  Jonathan T Lei  2 ,  Jin Cao  3 ,  Purba Singh  1 ,  Jianheng Peng  4 ,  Hilda Kennedy  1 ,  Nhu-Chau Nguyen  1 ,  Yue Chen  5 ,  Philip Lavere  3 ,  Jing Li  1 ,  Xin-Hui Du  6 ,  Burcu Cakar  1 ,  Wei Song  1 ,  Beom-Jun Kim  1 ,  Jiejun Shi  1 ,  Sinem Seker  1 ,  Doug W Chan  7 ,  Guo-Qiang Zhao  8 ,  Xi Chen  3 ,  Kimberly C Banks  9 ,  Richard B Lanman  9 ,  Maryam Nemati Shafaee  1 ,  Xiang H-F Zhang  7 ,  Suhas Vasaikar  1 ,  Bing Zhang  1 ,  Susan G Hilsenbeck  1 ,  Wei Li  1 ,  Charles E Foulds  10 ,  Matthew J Ellis  11 ,  Eric C Chang  12
Affiliations
  • 1. Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • 2. Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.
  • 3. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 4. Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Department of Physical Examination, the First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
  • 5. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA.
  • 6. Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Department of Bone and Soft Tissue, Zhengzhou University Affiliated Henan Cancer Hospital and College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, P. R. China.
  • 7. Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 8. Department of Bone and Soft Tissue, Zhengzhou University Affiliated Henan Cancer Hospital and College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, P. R. China.
  • 9. Guardant Health, Redwood City, CA, USA.
  • 10. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA.
  • 11. Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA. Electronic address: [email protected].
  • 12. Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Electronic address: [email protected].
PMID: 32142667 DOI: 10.1016/j.ccell.2020.02.003
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.
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