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Development of chemically modified peptide targeting BIG3-PHB2 interaction on estrogen-dependent breast cancer

ABSTRACT: Our previous studies demonstrated that specific inhibition of the BIG3-PHB2 complex, which is indispensable for estrogen (E2)-signaling activation, using ERAP, a dominant-negative peptide inhibitor, leads to the suppression of E2-dependent breast cancer cell growth in vitro and in vivo. However, duration of its effect is very short for clinical use. Here, we developed the chemically modified ERAP using stapling methods (stERAP; stapled ERAP) to improve duration of their antitumor effects. Tumor bearing mice treated with every 4 and 7 days with stERAP (1 mg/kg body weight) treatment effectively prevented the BIG3-PHB2 interaction, thereby releasing PHB2 to directly bind to both nuclear- and cytoplasmic ERalpha. This event led to the complete suppression of the E2-signalling pathways and ERalpha-positive breast cancer cell growth both in vitro and in vivo, but did not suppress the growth of normal mammary epithelial cells. Our findings suggest that the chemically modified stERAP may be a promising anti-tumor drug to suppress the growth of luminal-type breast cancer in clinical use.

ORGANISM(S): Homo sapiens

PROVIDER: GSE87378 | GEO | 2017/06/09

SECONDARY ACCESSION(S): PRJNA344561

REPOSITORIES: GEO

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Dietary ligands diindolylmethane and resveratrol result in diverse ERα signaling not seen after E2 and a subset of diindolylmethane mediated signaling needs concurrent AHR activation. [RNA-Seq]

Project description:Abstract: Inhibitory crosstalk between estrogen receptor alpha (ERalpha) and aryl hydrocarbon receptor (AHR) regulates 17β-estradiol (E2)-dependent breast cancer cell signalling. ERalpha and AHR are transcription factors activated by E2 and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) respectively. Dietary ligands resveratrol (RES) and 3,3´diindolylmethane (DIM) also activate ERalpha while only DIM activates AHR and RES represses it. DIM and RES are reported to have anti-cancer and anti-inflammatory properties. Studies with genome wide targets and AHR and ERalpha regulated genes after DIM and RES are unknown. We used chromatin immunoprecipitation with high-throughput sequencing and transcriptomics to study ERalpha as well as AHR coregulation in MCF-7 human breast cancer cells treated with DIM, RES, E2 or TCDD alone or E2+TCDD for 1 and 6 hours respectively. ERalpha bound sites after DIM enriched for the AHR motif but not after E2 or RES while AHR bound sites after DIM and E2+TCDD enriched for the ERE motif but not after TCDD. More than 90% of the differentially expressed genes closest to an AHR binding site after DIM or E2+TCDD also had an ERalpha site and 60% of coregulated genes between DIM and E2+TCDD were common. Collectively our data shows that RES and DIM differentially regulate multiple transcriptomic targets via ERalpha and ERalpha/AHR coactivity respectively, which need to be considered to properly interpret their cellular and biological responses. These novel data also suggest that when both receptors are activated, ERalpha dominates with preferential recruitment of AHR to ERalpha target genes.

2023-10-16 | GSE232233 | GEO

Homo sapiens

Project description:Development of chemically modified peptide targeting BIG3-PHB2 interaction on estrogen-dependent breast cancer

| PRJNA344561 | ENA

Response to estradiol-ERalpha ERE Binding defective mutant

Project description:In addition to the estrogen responsive element (ERE)-dependent gene expression, E2-ERalpha regulates transcription through functional interactions with transfactors bound to their cognate regulatory elements on DNA, hence the ERE-independent signaling pathway. However, the relative importance of the ERE-independent pathway in E2-ERalpha signaling is unclear. Our studies in infected ER-negative cell models with an ERalpha mutant (ERalpha 203/204/211E) that functions exclusively at the ERE-independent pathway demonstrated that genomic responses assessed by microarrays from the ERE-independent pathway to E2-ERalpha are not sufficient to alter cellular growth, death or motility. These findings suggest that the ERE-dependent pathway is the canonical E2-ERalpha signaling in model cell lines. Keywords: MDA-MB-231 cells

2007-12-04 | GSE9758 | GEO

An H3K4me3 reader, BAP18 as an adaptor of COMPASS-like core subunits co-activates ERa action to confer to tamoxifen resistance in breast cancer

Project description:Estrogen receptor alpha (ERalpha signaling pathway is essential for ERalpha positive breast cancer progression and endocrine therapy resistance. BPTF associated protein of 18kDa (BAP18) has been recognized as a crucial H3K4me3 reader. However, the whole genomic occupation of BAP18 and its biological function in breast cancer are still elusive. Here, we found that higher expression of BAP18 in ERalpha positive breast cancer is positively correlated with poor prognosis. ChIP-seq analysis further demonstrated that the half estrogen response elements (EREs) and the CCCTC binding factor (CTCF) binding sites are the significant enrichment sites found in estrogen-induced BAP18 binding sites. In addition, we provide the evidence to demonstrate that BAP18 as a novel co-activator of ERalpha is required for the recruitment of COMPASS-like core subunits to cis-regulatory element of ERalpha target genes in breast cancer cells. BAP18 is recruited to the promoter regions of estrogen-induced genes, accompanied with the enrichment of the lysine 4-trimethylated histone H3 tail (H3K4me3) in the presence of E2. Furthermore, BAP18 promotes cell growth and confers to ERalpha antagonist tamoxifen resistancein ERalpha positive breast cancer. Our data suggest that BAP18 facilitates the association between ERalpha and COMPASS-like core subunits, which might be an essential epigenetic therapeutic target for breast cancer.

2020-11-09 | GSE144641 | GEO

Estrogen effects on MCF-7 breast cancer cells co-expressing ERa and ERb

Project description:Two subtypes of the estrogen receptor, ERalpha and ERbeta, mediate the actions of estrogens, and the majority of human breast tumors contain both ERalpha and ERbeta. To examine the possible interactions and modulatory effects of ERbeta on ERalpha activity, we have used adenoviral gene delivery to produce human breast cancer (MCF-7) cells expressing ERbeta, along with their endogenous ERalpha. We have examined the effects of ERβ expression on genome-wide gene expression by Affymetrix GeneChip microarrays. We find that ERbeta modulated estrogen gene expression on nearly 24% of E2-stimulated genes but only 8% of E2-inhibited genes. We find that ERbeta modulation is gene-specific, enhancing or counteracting ERalpha regulation for distinct subsets of estrogen target genes. Introduction of ERbeta into ERalpha-containing cells induced up/down-regulation of many estrogen target in the absence of any added ligand. In addition, ERbeta presence elicited the expression of a unique set of genes that were not regulated by ERalpha alone. ERbeta modulated the expression of genes in many functional categories, but the greatest numbers were associated with transcription factor and signal transduction pathways. Regulation of multiple components in the TGF beta, SDF1, and semaphorin pathways, may contribute to the suppression of proliferation observed with ERbeta both in the presence and absence of estrogen. Hence, ERbeta modulates ERalpha gene regulation in diverse ways that may contribute to its growth-inhibiting beneficial effects in breast cancer Keywords: modulatory effects of ERb on ERa

2006-08-10 | GSE4006 | GEO

Gene expression profiles of CARM1 overexpression in MCF7

Project description:The goal of this study is to identify ERalpha-target genes affected by overexpression of the histone arginine methyltransferase CARM1 in breast cancer cells. The roles of CARM1 in ERalpha+ breast cancer was not well characterized. Therefore, we created a Dox inducible CARM1 overexpressing MCF7 cell line where CARM1 is overexpressed by 2 fold to determine the created a Dox-inducible CARM1 overexpressing MCF7 cells for evaluation of the global effects of CARM1 on Eralpha-target gene expression. MCF7-tet-on-CARM1 clone 13 were treated under 4 conditions: DMSO; Dox; E2 (10nM); Dox+E2. In Dox+E2 condition, cells were pre-treated with Dox for 5 days before treating with E2 for 4 hours. 3 biological replicates were included and total of 12 samples were analyzed.

2011-06-01 | E-GEOD-26454 | biostudies-arrayexpress

Gene expression profiles of MCF7 with CARM1 knocked down

Project description:The goal of this study is to identify ERalpha-target genes affected by knocking down of the histone arginine methyltransferase CARM1 in MCF7 breast cancer cells. The roles of CARM1 in ERalpha+ breast cancer was not well characterized. Therefore, we created a Dox inducible CARM1 knockingdown MCF7 cell line where CARM1 is decreased to 20% of endogeneous level to determine the created a Dox-inducible CARM1shRNA overexpressing MCF7 cells for evaluation of the global effects of CARM1 on ERalpha-target gene expression. MCF7-tet-on-CARM1shRNA clone 1 were treated under 4 conditions: DMSO; Dox; E2 (10nM); Dox+E2. In Dox+E2 condition, cells were pre-treated with Dox for 5 days before treating with E2 for 4 hours. 3 biological replicates were included and total of 12 samples were analyzed.

2011-06-01 | E-GEOD-26259 | biostudies-arrayexpress

Response to estradiol-ERalpha

2007-12-04 | GSE9757 | GEO

Cellular reprogramming by the conjoint action of ERalpha, FOXA1 and GATA3 to a ligand-inducible growth state

Project description:Despite the role of the estrogen receptor alpha (ERalpha) pathway as a key growth driver for breast cells, the phenotypic consequence of exogenous introduction of ERalpha into ERalpha-negative cells paradoxically has been growth inhibition. We map the binding profiles of ERalpha and its interacting transcription factors (TFs), FOXA1 and GATA3, in MCF-7 breast carcinoma cells. We observe that these three TFs form a functional enhanceosome and cooperatively modulate the transcriptional networks previously ascribed to ERalpha alone. We demonstrate that these enhanceosome-occupied sites are associated with optimal enhancer characteristics with highest p300 coactivator recruitment, RNA Pol II occupancy, and chromatin opening. The enhancesome binding sites appear to regulate the genes driving core ERalpha function. Most importantly, we show that transfection of all three TFs was necessary to reprogram the ERalpha-negative MDA-MB-231 and BT-459 cells to restore the estrogen responsive growth and to transcriptionally resemble the estrogen-treated ERalpha-positive MCF-7 cells. Cumulatively, these results suggest that all of the enhanceosome components comprising ERalpha, FOXA1 and GATA3 are necessary for the full repertoire of the cancer-associated effects of the ERalpha. The analysis of ERalpha, FOXA1, and GATA3 in MCF-7 cancer cells was done by ChIP-seq data obtained either with estradiol (E2) stimulation or without stimulation using vehicle as a control. Using the ERalpha bindings defined by ChIP-seq (GSE23893), FOXA1 bindings (GSE26831), and GATA3 bindings (this Series), we analyzed the enhanceosome effect of the overlapped binding sites from ERalpha, FOXA1 and GATA3.

2011-09-05 | E-GEOD-29073 | biostudies-arrayexpress

Anti-prolif. effect of E2 in breast cancer cells that re-exp. ERalpha is mediated by aberr. regulat. of cell cycle genes

Project description:Gene expression changes caused by estrogen treatment of breast cancer cells that re-express ERalpha was investigated by infecting ER-negative MDA-MB-231 breast cancer cells for 24 h with recombinant adenovirus encoding full-length human ERalpha (Ad-ERalpha) or control vector (Ad-LacZ), and treating them with 0·01% ethanol (vehicle control) or 10-8 M 17beta-estradiol (E2). After 48 h of treatment, total RNA was isolated and used for transcript profiling on Affymetrix GeneChips. Three independent biological replicates of this experiment were carried out. Keywords: ordered

2005-02-09 | GSE2251 | GEO

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