ETV4 is necessary for estrogen signaling and growth in endometrial cancer cells

Rodriguez, Adriana C.; Vahrenkamp, Jeffery M.; Berrett, Kristofer C.; Clark, Kathleen; Guillen, Katrin P.; Scherer, Sandra D.; Yang, Chieh-Hsiang; Welm, Bryan E.; Janát-Amsbury, Margit M.; Graves, Barbara J.; Gertz, Jason

doi:10.1101/617142

Cited by 11 publications

(24 citation statements)

References 55 publications

(63 reference statements)

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“…In addition, our study focused on a particular endometrial cancer cell line, Ishikawa, and the effects of ESR1 mutations may be different in different models. We recently found that ESR1 genomic binding is consistent between endometrial tumors and distinct from breast tumors, with Ishikawa exhibiting a clear endometrial cancer ESR1 binding pattern (Rodriguez et al 2019a), suggesting that our findings could be generally applicable. In summary, our study has led to the creation of isogenic models of mutant ESR1 in endometrial cancer cells, the confirmation of estrogen-independent mutant ESR1 activity, and the discovery of novel gene regulation through mutant ESR1 that cannot be explained by constant activity alone.…”

Section: A B C Dsupporting

confidence: 51%

“…The molecular consequences of ESR1 LBD mutations have not been explored in endometrial cancer and warrant investigation. We used a CRISPR/Cas9-mediated epitope tagging strategy called CETCH-seq (Savic et al 2015) in Ishikawa cells, an endometrial adenocarcinoma cell line that exhibits ESR1 genomic binding similar to endometrial tumor samples (Rodriguez et al 2019a), to model a common ESR1 LBD mutation, D538G. This technique combines guide RNAs that target Cas9 to the C terminus of ESR1 and a donor plasmid that leads to the incorporation of a 3X FLAG epitope tag and neomycin resistance gene at ESR1's endogenous locus ( Fig.…”

Section: Generation Of D538g Esr1 Mutant and Wild-type Cell Linesmentioning

confidence: 99%

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Estrogen-independent molecular actions of mutant estrogen receptor 1 in endometrial cancer

et al. 2019

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Estrogen receptor 1 (ESR1) mutations have been identified in hormone therapy-resistant breast cancer and primary endometrial cancer. Analyses in breast cancer suggest that mutant ESR1 exhibits estrogen-independent activity. In endometrial cancer, ESR1 mutations are associated with worse outcomes and less obesity, however, experimental investigation of these mutations has not been performed. Using a unique CRISPR/Cas9 strategy, we introduced the D538G mutation, a common endometrial cancer mutation that alters the ligand binding domain of ESR1, while epitope tagging the endogenous locus. We discovered estrogen-independent mutant ESR1 genomic binding that is significantly altered from wild-type ESR1. The D538G mutation impacted expression, including a large set of nonestrogen-regulated genes, and chromatin accessibility, with most affected loci bound by mutant ESR1. Mutant ESR1 is distinct from constitutive ESR1 activity because mutant-specific changes are not recapitulated with prolonged estrogen exposure. Overall, the D538G mutant ESR1 confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells that are distinct from breast cancer cells.

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Section: A B C Dsupporting

confidence: 51%

Section: Generation Of D538g Esr1 Mutant and Wild-type Cell Linesmentioning

confidence: 99%

Estrogen-independent molecular actions of mutant estrogen receptor 1 in endometrial cancer

et al. 2019

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“…Analysis of additional factors bound to these regions indicates that p300 is bound to CISH-2 and MMP17-1, the sites responsible for acetylation of the neighborhood. NFIC and ETV4 ( 35 ) were also uniquely found at CISH-2 and MMP17-1 as opposed to CISH-1 and MMP17-2. An expanded genome-wide analysis of ERBS, split by H3K27ac overlap, uncovered strong enrichment of EGR1, NFIC, MAX, TCF12, USF1, ETV4 and SRF at ERBS that overlap with H3K27ac compared to ERBS without H3K27ac.…”

Section: Discussionmentioning

confidence: 95%

Regulatory sharing between estrogen receptor α bound enhancers

Carleton

Ginley-Hidinger

Berrett

et al. 2020

Nucleic Acids Research

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Abstract The human genome encodes an order of magnitude more gene expression enhancers than promoters, suggesting that most genes are regulated by the combined action of multiple enhancers. We have previously shown that neighboring estrogen-responsive enhancers exhibit complex synergistic contributions to the production of an estrogenic transcriptional response. Here we sought to determine the molecular underpinnings of this enhancer cooperativity. We generated genetic deletions of four estrogen receptor α (ER) bound enhancers that regulate two genes and found that enhancers containing full estrogen response element (ERE) motifs control ER binding at neighboring sites, while enhancers with pre-existing histone acetylation/accessibility confer a permissible chromatin environment to the neighboring enhancers. Genome engineering revealed that two enhancers with half EREs could not compensate for the lack of a full ERE site within the cluster. In contrast, two enhancers with full EREs produced a transcriptional response greater than the wild-type locus. By swapping genomic sequences, we found that the genomic location of a full ERE strongly influences enhancer activity. Our results lead to a model in which a full ERE is required for ER recruitment, but the presence of a pre-existing permissible chromatin environment can also be needed for estrogen-driven gene regulation to occur.

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“…ETV4, a member of the PEA3 subgroup of the ETS transcription factor family, 26 plays important roles in regulating gene expression during early embryogenesis, 27 obesity, and diabetes, 28 as well as oncogenesis, 29,30 and its overexpression is involved in the malignant transformation of cells and enhanced tumor cell invasion. 31,32 According to a recent study, ETV4 promotes the migration and metastasis of clear-cell renal-cell carcinoma in vitro and in vivo. 33 However, research studies on the expression of ETV4 in cervical cancer are rare.…”

Section: Discussionmentioning

confidence: 99%

Discovery of key genes as novel biomarkers specifically associated with HPV-negative cervical cancer

Liu

Jiang

et al. 2021

Molecular Therapy - Methods & Clinical Development

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Cervical cancer is a common female malignancy that is mainly caused by human papillomavirus (HPV) infection. However, the incidence of HPV-negative cervical cancer has shown an increasing trend in recent years. Because the mechanism of HPV-negative cervical cancer development is unclear, this study aims to find the pattern of differential gene expression in HPV-negative cervical cancer and verify the underlying potential mechanism. Differentially expressed genes were compared among HPV-positive cervical cancer, HPV-negative cervical cancer, and normal cervical tissues retrieved from TCGA. Subsequently, dysregulated differentially expressed genes specifically existed in HPV-negative cervical cancer tissues and HPV-negative cell lines were validated by qRT-PCR, western blotting, and immunohistochemical staining. We found seventeen highly expressed genes that were particularly associated with HPV-negative cervical cancer from analysis of TCGA database. Among the 17 novel genes, 7 genes (preferentially expressed antigen in melanoma [PRAME], HMGA2, ETS variant 4 [ETV4], MEX3A, TM7SF2, SLC19A1, and tweety-homologs 3 [TTYH3]) displayed significantly elevated expression in HPV-negative cervical cancer cells and HPV-negative cervical cancer tissues. Additionally, higher expression of MEX3A and TTYH3 was associated with a shorter overall survival of patients with HPV-negative cervical cancer. Our study implies that these seven genes are more likely to provide novel insights into the occurrence and progression of HPV-negative cervical cancer.

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ETV4 is necessary for estrogen signaling and growth in endometrial cancer cells

Cited by 11 publications

References 55 publications

Estrogen-independent molecular actions of mutant estrogen receptor 1 in endometrial cancer

Estrogen-independent molecular actions of mutant estrogen receptor 1 in endometrial cancer

Regulatory sharing between estrogen receptor α bound enhancers

Discovery of key genes as novel biomarkers specifically associated with HPV-negative cervical cancer

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