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Inhibition of heregulin mediated MCF-7 breast cancer cell growth by the ErbB3 binding protein EBP1.

ABSTRACT: The ErbB2/3 heterodimer plays a critical role in breast cancer genesis and progression. EBP1, an ErbB3 binding protein, inhibits breast cancer growth but its effects on ErbB3 ligand mediated signal transduction or ErbB receptors is not known. We report here that ectopic expression of EBP1 in MCF-7 and AU565 breast cancer cell lines inhibited HRG-induced proliferation. ErbB2 protein levels were substantially decreased in EBP1 transfectants, while ErbB3 levels were unchanged. HRG-induced AKT activation was attenuated in EBP1 stable transfectants and transfection of a constitutively activated AKT partially restored the growth response to HRG. Down-regulation of EBP1 expression in MCF-7 cells by shRNA resulted in increased cell growth in response to HRG and increased cyclin D1 and ErbB2 expression. These results suggest that EBP1, by down-regulating ErbB signal transduction, attentuates HRG-mediated growth of breast cancer cells.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC2464455 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Inhibition of heregulin mediated MCF-7 breast cancer cell growth by the ErbB3 binding protein EBP1.

Zhang Yuexing Y Akinmade Damilola D Hamburger Anne W AW

Cancer letters 20080319 2

The ErbB2/3 heterodimer plays a critical role in breast cancer genesis and progression. EBP1, an ErbB3 binding protein, inhibits breast cancer growth but its effects on ErbB3 ligand mediated signal transduction or ErbB receptors is not known. We report here that ectopic expression of EBP1 in MCF-7 and AU565 breast cancer cell lines inhibited HRG-induced proliferation. ErbB2 protein levels were substantially decreased in EBP1 transfectants, while ErbB3 levels were unchanged. HRG-induced AKT activ ...[more]

PMID: 18355957

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Specificity and heregulin regulation of Ebp1 (ErbB3 binding protein 1) mediated repression of androgen receptor signalling.

Project description:Although ErbB receptors have been implicated in the progression of prostate cancer, little is known about proteins that may mediate their interactions with the androgen receptor (AR). Ebp1, a protein cloned via its association with the ErbB3 receptor, binds the AR and inhibits androgen-regulated transactivation of wild-type AR in COS cells. As the complement of coregulators in different cells are important for AR activity, we determined the effect of Ebp1 on AR function in prostate cancer cell lines. In addition, we examined the regulation of Ebp1 function by the ErbB3/4 ligand heregulin (HRG). In this study, we demonstrate, using several natural AR-regulated promoters, that Ebp1 repressed transcriptional activation of wild-type AR in prostate cancer cell lines. Downregulation of Ebp1 expression in LNCaP cells using siRNA resulted in activation of AR in the absence of androgen. Ebp1 associated with ErbB3 in LNCaP cells in the absence of HRG, but HRG induced the dissociation of Ebp1 from ErbB3. In contrast, HRG treatment enhanced both the association of Ebp1 with AR and also the ability of Ebp1 to repress AR transactivation. These studies suggest that Ebp1 is an AR corepressor whose biological activity can be regulated by the ErbB3 ligand, HRG.

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Alterations in cell growth and signaling in ErbB3 binding protein-1 (Ebp1) deficient mice.

Project description:The ErbB3 binding protein-1 (Ebp1) belongs to a family of DNA/RNA binding proteins implicated in cell growth, apoptosis and differentiation. However, the physiological role of Ebp1 in the whole organism is not known. Therefore, we generated Ebp1-deficient mice carrying a gene trap insertion in intron 2 of the Ebp1 (pa2g4) gene.Ebp1-/- mice were on average 30% smaller than wild type and heterozygous sex matched littermates. Growth retardation was apparent from Day 10 until Day 30. IGF-1 production and IGBP-3 and 4 protein levels were reduced in both embryo fibroblasts and adult knock-out mice. The proliferation of fibroblasts derived from Day 12.5 knock out embryos was also decreased as compared to that of wild type cells. Microarray expression analysis revealed changes in genes important in cell growth including members of the MAPK signal transduction pathway. In addition, the expression or activation of proliferation related genes such as AKT and the androgen receptor, previously demonstrated to be affected by Ebp1 expression in vitro, was altered in adult tissues.These results indicate that Ebp1 can affect growth in an animal model, but that the expression of proliferation related genes is cell and context specific. The Ebp1-/- mouse line represents a new in vivo model to investigate Ebp1 function in the whole organism.

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Repression of E2F1-mediated transcription by the ErbB3 binding protein Ebp1 involves histone deacetylases.

Project description:Ebp1, an ErbB3 binding protein that is a member of the proliferation-associated PA2G4 family, inhibits the proliferation and induces the differentiation of human ErbB positive breast and prostate cancer cell lines. Ebp1 binds the tumor suppressor retinoblastoma protein (Rb) both in vivo and in vitro, and Rb and Ebp1 cooperate to inhibit the transcription of the E2F1-regulated cyclin E promoter. We show here that Ebp1 can inhibit the transcription of other E2F-regulated reporter genes and of several endogenous E2F-regulated genes important in cell cycle progression in both Rb positive and Rb null cells. The Ebp1-mediated transcriptional repression depended on the presence of an E2F1 consensus element in the promoters. A fusion of Ebp1 with the GAL4 DNA binding domain protein had independent transcriptional repression activity that mapped to the C-terminal region of Ebp1. This C-terminal region of Ebp1 bound functional histone deacetylase (HDAC) activity and inhibitors of HDAC significantly reduced Ebp1-mediated repression. Ebp1 bound HDAC2, but not HDAC1, in vitro. An Ebp1 mutant lacking the HDAC binding domain failed to inhibit transcription. Our results suggest that Ebp1 can repress transcription of some E2F-regulated promoters and that one mechanism of Ebp1- mediated transcriptional repression is via its ability to recruit HDAC activity.

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| S-EPMC6755798 | biostudies-literature

Alterations in Cell Growth and Signaling in ErbB3 Binding Protein -1 (Ebp1) Deficient Mice

Project description:Background: The ErbB3 binding protein-1 (Ebp1) belongs to a family of DNA/RNA binding proteins implicated in cell growth, apoptosis and differentiation. However, the physiological role of Ebp1 in the whole organism is not known. Therefore, we generated Ebp1-deficient mice carrying a gene trap insertion in intron 2 of the Ebp1 (pa2g4) gene. Results: Ebp1 -/- mice were on average 30% smaller than wild type and heterozygous sex matched littermates. Growth retardation was apparent from Day 10 until Day 30. IGF-1 production and IGBP-3 and 4 protein levels were reduced in both embryo fibroblasts and adult knock-out mice. The proliferation of fibroblasts derived from Day 12.5 knock out embryos was also decreased as compared to that of wild type cells. Microarray expression analysis revealed changes in genes important in cell growth including members of the MAPK signal transduction pathway. In addition, the expression or activation of proliferation related genes such as AKT and the androgen receptor, previously demonstrated to be affected by Ebp1 expression in vitro, were altered in adult tissues. Conclusions: These results indicate that Ebp1 can affect growth in an animal model, but that the expression of proliferation related genes is cell and context specific. The Ebp1-/- mouse line represents a new in vivo model to investigate Ebp1 function in the whole organism.

2009-03-31 | GSE13718 | GEO

The ErbB3-binding protein Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells.

Project description:Down-regulation of the androgen receptor (AR) is being evaluated as an effective therapy for the advanced stages of prostate cancer. We report that Ebp1, a protein identified by its interactions with the ErbB3 receptor, down-regulates expression of AR and AR-regulated genes in the LNCaP prostate cancer cell line. Using microarray analysis, we identified six endogenous AR target genes, including the AR itself, that are down-regulated by ebp1 overexpression. Chromatin immunoprecipitation assays revealed that Ebp1 was recruited to the prostate-specific antigen gene promoter in response to the androgen antagonist bicalutamide, suggesting that Ebp1 directly affected the expression of AR-regulated genes in response to androgen antagonists. Ebp1 expression was reduced in cells that had become androgen-independent. Androgens failed to stimulate either the growth of ebp1 transfectants or transcription of AR-regulated reporter genes in these cells. The agonist activity of the antiandrogen cyproterone acetate was abolished in ebp1 transfectants. In severe combined immunodeficient mice, Ebp1 overexpression resulted in a reduced incidence of LNCaP tumors and slower tumor growth. These findings suggest that Ebp1 is a previously unrecognized therapeutic target for treatment of hormone refractory prostate cancer.

| S-EPMC1175001 | biostudies-literature

The ErbB3-binding protein EBP1 modulates lapatinib sensitivity in prostate cancer cells.

Project description:Although ErbB receptors have been implicated in prostate cancer progression, ErbB-directed drugs have not proven effective for prostate cancer treatment. The ErbB3-binding protein EBP1 affects both ErbB2 and androgen receptor signaling, two components of the response to ErbB-targeted therapies. We therefore examined the effects of EBP1 expression on the response to the ErbB1/2 tyrosine kinase inhibitor lapatinib. We found a negative correlation between endogenous EBP1 levels and lapatinib sensitivity in prostate cancer cell lines. We then overexpressed or inhibited expression of EBP1. Silencing EBP1 expression increased lapatinib sensitivity and overexpression of EBP1 increased resistance in androgen-containing media. Androgen depletion resulted in an increased sensitivity of androgen-dependent EBP1 expressing cells to lapatinib, but did not affect the lapatinib sensitivity of hormone resistant cells. However, EBP1 silenced cells were still more sensitive to lapatinib than EBP1-expressing cells in the absence of androgens. The increase in sensitivity to lapatinib following EBP1 silencing was associated with increased ErbB2 levels. In addition, lapatinib treatment increased ErbB2 levels in sensitive cells that express low levels of EBP1, but decreased ErbB2 levels in resistant EBP1-expressing cells. In contrast, ErbB3 and phospho ErbB3 levels were not affected by either changes in EBP1 levels or lapatinib treatment. The production of the ErbB3/4 ligand heregulin was increased in EBP1-silenced cells. EBP1-induced changes in AR levels were not associated with changes in lapatinib sensitivity. These studies suggest that the ability of EBP1 to activate ErbB2 signaling pathways results in increased lapatinib sensitivity.

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Alterations in Cell Growth and Signaling in ErbB3 Binding Protein -1 (Ebp1) Deficient Mice

2009-03-31 | E-GEOD-13718 | biostudies-arrayexpress

The ErbB3 binding protein EBP1 regulates ErbB2 protein levels and tamoxifen sensitivity in breast cancer cells.

Project description:The ErbB2/3 heterodimer plays a critical role in breast cancer progression and in the development of endocrine resistance. EBP1, an ErbB3 binding protein, inhibits HRG-stimulated breast cancer growth, decreases ErbB2 protein levels and contributes to tamoxifen sensitivity. We report here that ectopic expression of EBP1 in Estrogen Receptor (ER) positive breast cancers that express ErbB2 at both high and low levels decreased ErbB2 protein levels. ErbB2 protein expression was also increased in mammary glands of Ebp1 knock out mice. To define the mechanism of ErbB2 down regulation, we examined the effects of EBP1 on ErbB2 mRNA levels, transcription of the ErbB2 gene and ErbB2 protein stability. We found that ectopic expression of EBP1 decreased steady state levels of endogenous ErbB2 mRNA in all cell lines tested. EBP1 overexpression decreased the activity of an ErbB2 promoter reporter in cells which overxpress ErbB2. However, reporter activity was unchanged or increased in cells which express low endogenous levels of ErbB2. We also found that ectopic expression of EBP1 accelerated ErbB2 protein degradation and enhanced ErbB2 ubiquitination in cells which express both low and high levels of ErbB2. Treatment with proteasome inhibitors prevented this decrease in ErbB2 protein levels. Ablation of EBP1 expression led to tamoxifen resistance that was abrogated by inhibition of ErbB2 activity. These results suggest that EBP1 inhibits expression of ErbB2 protein levels by multiple mechanisms and that EBP1's effects on tamoxifen sensitivity are mediated in part by its ability to modulate ErbB2 levels.

| S-EPMC3709471 | biostudies-other

Roles of ErbB3-binding protein 1 (EBP1) in embryonic development and gene-silencing control.

Project description:ErbB3-binding protein 1 (EBP1) is implicated in diverse cellular functions, including apoptosis, cell proliferation, and differentiation. Here, by generating genetic inactivation of Ebp1 mice, we identified the physiological roles of EBP1 in vivo. Loss of Ebp1 in mice caused aberrant organogenesis, including brain malformation, and death between E13.5 and 15.5 owing to severe hemorrhages, with massive apoptosis and cessation of cell proliferation. Specific ablation of Ebp1 in neurons caused structural abnormalities of brain with neuron loss in [Nestin-Cre; Ebp1 flox/flox ] mice. Notably, global methylation increased with high levels of the gene-silencing unit Suv39H1/DNMT1 in Ebp1-deficient mice. EBP1 repressed the transcription of Dnmt1 by binding to its promoter region and interrupted DNMT1-mediated methylation at its target gene, Survivin promoter region. Reinstatement of EBP1 into embryo brain relived gene repression and rescued neuron death. Our findings uncover an essential role for EBP1 in embryonic development and implicate its function in transcriptional regulation.

| S-EPMC6900500 | biostudies-literature

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