Dataset Information

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

ABSTRACT: We report that neurofibromin, a tumor suppressor and Ras-GAP (GTPase-activating protein), is also an estrogen receptor-? (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.

SUBMITTER: Zheng ZY

PROVIDER: S-EPMC7286719 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Zheng Ze-Yi ZY Anurag Meenakshi M Lei Jonathan T JT Cao Jin J Singh Purba P Peng Jianheng J Kennedy Hilda H Nguyen Nhu-Chau NC Chen Yue Y Lavere Philip P Li Jing J Du Xin-Hui XH Cakar Burcu B Song Wei W Kim Beom-Jun BJ Shi Jiejun J Seker Sinem S Chan Doug W DW Zhao Guo-Qiang GQ Chen Xi X Banks Kimberly C KC Lanman Richard B RB Shafaee Maryam Nemati MN Zhang Xiang H-F XH Vasaikar Suhas S Zhang Bing B Hilsenbeck Susan G SG Li Wei W Foulds Charles E CE Ellis Matthew J MJ Chang Eric C EC

Cancer cell 20200305 3

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<sup>+</sup> ...[more]

PMID: 32142667

Similar Datasets

Project description:BackgroundSin3A is an evolutionarily conserved transcriptional repressor which regulates gene expression as part of the multi-protein Sin3 repressive complex. It functions as a scaffold upon which proteins with enzymatic activity dock, including chromatin modifying histone deacetylases. Although regulation of transcription by Sin3A has been studied in detail, little is understood about the function of Sin3A in cancer cells. We previously showed that Sin3A is expressed in breast cancer cells and is a repressor of estrogen receptor-alpha (ERα, ESR1) gene expression. Here, we expand our previous studies to elucidate the function of Sin3A in the control of gene expression and growth of breast cancer cells.ResultsAnalysis of gene expression following knockdown of Sin3A revealed changes in both basal and regulated gene transcription. Genes of known importance in breast cancer and estrogen signaling, including ERBB2, PGR, MYC, CLU, and NCOA2, were among those identified as Sin3A-responsive. The mechanism of Sin3A action varied among genes and was found to be mediated through both HDAC1/2 -dependent and -independent activities. Loss of Sin3A inhibited breast cancer cell growth by increasing apoptosis without affecting cell cycle progression. Analysis of both ERα-positive and ERα-negative cell lines revealed that the effects of Sin3A on growth were cell-type specific, as Sin3A expression promoted maximum growth of only the ERα-positive cells, and, notably, Sin3A protein itself was increased by estrogen. Further gene expression experiments revealed that Sin3A repressed expression of key apoptotic genes, including TRAIL, TRAILR1, CASP10, and APAF1, in ERα-positive, but not ERα-negative, cell lines, which could provide a mechanistic explanation for cell-type differences in growth.ConclusionsThis study identifies Sin3A as a regulator of gene expression, survival, and growth in ERα-positive breast cancer cells. Sin3A regulates the transcription of genes involved in breast cancer and apoptosis and acts through multiple mechanisms not limited to histone deacetylase function. These findings reveal previously undescribed functions of Sin3A in breast cancer and provide evidence for an important role of this transcriptional repressor in ERα-positive tumor cell growth.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets