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

Cancer Cell
Ze-Yi ZhengEric 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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Citations

May 23, 2020·British Journal of Cancer·Jean-Philippe BrosseauLu Q Le
Sep 17, 2020·Cancer Research·Poornima Bhat-NakshatriHarikrishna Nakshatri
Oct 25, 2020·Cancers·Arianna Bellazzo, Licio Collavin
Mar 21, 2021·Nature Communications·Liliana Garcia-MartinezLluis Morey
Mar 30, 2021·Frontiers in Oncology·Kevin Roarty, Gloria V Echeverria
Mar 31, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Argun AkcakanatFunda Meric-Bernstam

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