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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. Cons...

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Published in:Cancer cell 2020-03, Vol.37 (3), p.387-402.e7
Main Authors: Zheng, Ze-Yi, Anurag, Meenakshi, Lei, Jonathan T., Cao, Jin, Singh, Purba, Peng, Jianheng, Kennedy, Hilda, Nguyen, Nhu-Chau, Chen, Yue, Lavere, Philip, Li, Jing, Du, Xin-Hui, Cakar, Burcu, Song, Wei, Kim, Beom-Jun, Shi, Jiejun, Seker, Sinem, Chan, Doug W., Zhao, Guo-Qiang, Chen, Xi, Banks, Kimberly C., Lanman, Richard B., Shafaee, Maryam Nemati, Zhang, Xiang H.-F., Vasaikar, Suhas, Zhang, Bing, Hilsenbeck, Susan G., Li, Wei, Foulds, Charles E., Ellis, Matthew J., Chang, Eric C.
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cited_by cdi_FETCH-LOGICAL-c459t-439dc9cf1ba0046a93da9eec78be11e9218e5473327287d85d997ebfd5f53bd13
cites cdi_FETCH-LOGICAL-c459t-439dc9cf1ba0046a93da9eec78be11e9218e5473327287d85d997ebfd5f53bd13
container_end_page 402.e7
container_issue 3
container_start_page 387
container_title Cancer cell
container_volume 37
creator Zheng, Ze-Yi
Anurag, Meenakshi
Lei, Jonathan T.
Cao, Jin
Singh, Purba
Peng, Jianheng
Kennedy, Hilda
Nguyen, Nhu-Chau
Chen, Yue
Lavere, Philip
Li, Jing
Du, Xin-Hui
Cakar, Burcu
Song, Wei
Kim, Beom-Jun
Shi, Jiejun
Seker, Sinem
Chan, Doug W.
Zhao, Guo-Qiang
Chen, Xi
Banks, Kimberly C.
Lanman, Richard B.
Shafaee, Maryam Nemati
Zhang, Xiang H.-F.
Vasaikar, Suhas
Zhang, Bing
Hilsenbeck, Susan G.
Li, Wei
Foulds, Charles E.
Ellis, Matthew J.
Chang, Eric C.
description 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.
doi_str_mv 10.1016/j.ccell.2020.02.003
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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. 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chemistry</subject><subject>Neurofibromin 1 - genetics</subject><subject>Neurofibromin 1 - metabolism</subject><subject>NF1</subject><subject>RAS</subject><subject>ras Proteins - metabolism</subject><subject>Signal Transduction</subject><subject>Tamoxifen - pharmacology</subject><subject>Xenograft Model Antitumor Assays</subject><subject>yeast</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kF9K5EAQhxtZccZZT7AguUCy_SdJpx8U3EFXQRTE9bXpdFdme8ikQ3UUPJYX8Uy2zq7oi09VUPX9ivoI-cFowSirf64La6HvC045LSgvKBU7ZM4a2eSibupvqa9EldeMNjOyH-OaJopJtUdmgrOS17Wck7sruMfQ-RbDxg_ZRczMkJ3GCcMKhuwGLIxTwPz5KbtFM0SLfpx8GEyfLUOOMCLEGDBL6C8EE6dsaQYL-J3sdqaPcPCvLsifs9Pb5Xl-ef37YnlymduyUlNeCuWssh1rDaVlbZRwRgFY2bTAGCjOGqhKKQSXvJGuqZxSEtrOVV0lWsfEghxvc8f7dgPOwjCh6fWIfmPwUQfj9efJ4P_qVXjQKa-WTKUAsQ2wGGJE6N5ZRvWrZr3Wb5r1q2ZNuU6aE3X48ew7899rWjjaLkB6_sED6mg9JDPOI9hJu-C_PPACAWOSZg</recordid><startdate>20200316</startdate><enddate>20200316</enddate><creator>Zheng, Ze-Yi</creator><creator>Anurag, Meenakshi</creator><creator>Lei, Jonathan T.</creator><creator>Cao, Jin</creator><creator>Singh, Purba</creator><creator>Peng, Jianheng</creator><creator>Kennedy, Hilda</creator><creator>Nguyen, Nhu-Chau</creator><creator>Chen, Yue</creator><creator>Lavere, Philip</creator><creator>Li, Jing</creator><creator>Du, Xin-Hui</creator><creator>Cakar, Burcu</creator><creator>Song, Wei</creator><creator>Kim, Beom-Jun</creator><creator>Shi, Jiejun</creator><creator>Seker, Sinem</creator><creator>Chan, Doug W.</creator><creator>Zhao, Guo-Qiang</creator><creator>Chen, Xi</creator><creator>Banks, Kimberly C.</creator><creator>Lanman, Richard B.</creator><creator>Shafaee, Maryam Nemati</creator><creator>Zhang, Xiang H.-F.</creator><creator>Vasaikar, Suhas</creator><creator>Zhang, Bing</creator><creator>Hilsenbeck, Susan G.</creator><creator>Li, Wei</creator><creator>Foulds, Charles E.</creator><creator>Ellis, Matthew J.</creator><creator>Chang, Eric C.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20200316</creationdate><title>Neurofibromin Is an Estrogen Receptor-α Transcriptional Co-repressor in Breast Cancer</title><author>Zheng, Ze-Yi ; Anurag, Meenakshi ; Lei, Jonathan T. ; Cao, Jin ; Singh, Purba ; Peng, Jianheng ; Kennedy, Hilda ; Nguyen, Nhu-Chau ; Chen, Yue ; Lavere, Philip ; Li, Jing ; Du, Xin-Hui ; Cakar, Burcu ; Song, Wei ; Kim, Beom-Jun ; Shi, Jiejun ; Seker, Sinem ; Chan, Doug W. ; Zhao, Guo-Qiang ; Chen, Xi ; Banks, Kimberly C. ; Lanman, Richard B. ; Shafaee, Maryam Nemati ; Zhang, Xiang H.-F. ; Vasaikar, Suhas ; Zhang, Bing ; Hilsenbeck, Susan G. ; Li, Wei ; Foulds, Charles E. ; Ellis, Matthew J. ; Chang, Eric C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-439dc9cf1ba0046a93da9eec78be11e9218e5473327287d85d997ebfd5f53bd13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Amino Acid Motifs</topic><topic>Animals</topic><topic>breast cancer</topic><topic>Breast Neoplasms - 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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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32142667</pmid><doi>10.1016/j.ccell.2020.02.003</doi><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1535-6108
ispartof Cancer cell, 2020-03, Vol.37 (3), p.387-402.e7
issn 1535-6108
1878-3686
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7286719
source BACON - Elsevier - GLOBAL_SCIENCEDIRECT-OPENACCESS
subjects Amino Acid Motifs
Animals
breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Breast Neoplasms - mortality
Breast Neoplasms - pathology
Cell Nucleus - drug effects
Cell Nucleus - metabolism
co-regulator
Co-Repressor Proteins
Drosophila
endocrine therapy
Estrogen Antagonists - pharmacology
estrogen receptor
Estrogen Receptor alpha - genetics
Estrogen Receptor alpha - metabolism
Female
GTPase
Humans
MCF-7 Cells
Mice, Nude
Mice, SCID
Mutation
neurofibromatosis
Neurofibromin 1 - chemistry
Neurofibromin 1 - genetics
Neurofibromin 1 - metabolism
NF1
RAS
ras Proteins - metabolism
Signal Transduction
Tamoxifen - pharmacology
Xenograft Model Antitumor Assays
yeast
title Neurofibromin Is an Estrogen Receptor-α Transcriptional Co-repressor in Breast Cancer
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