Ectopic expression of the ErbB-3 binding protein Ebp1 inhibits growth and induces differentiation of human breast cancer cell lines

Lessor, Tracy; Yoo, Joo‐Yeon; Xia, Xianmin; Woodford, Nicholas; Hamburger, Anne W.

doi:10.1002/(sici)1097-4652(200006)183:3<321::aid-jcp4>3.0.co;2-o

Cited by 85 publications

(84 citation statements)

References 30 publications

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“…Further study is needed of the involvement of non-NRG, non-ERBB regulators of ERBB3, such as CDK5, [122][123][124] BRK, 125 SRC, 126 and MET. 120 The fascinating and widely expressed ERBB3 effector EBP1 has thus far been examined mainly in mammary and prostate cells; [154][155][156][157][158][159][160][161][162][163][164] may it be important also in other cancers where ERBB3 is clearly a player, such as lung and melanoma? It is hoped that full understanding of the regulation and functions of ERBB3 will facilitate its integration into cancer management.…”

Section: Discussionmentioning

confidence: 99%

“…A functional story has emerged for EBP1 in human breast and prostate cancer cell lines, where high expression of EBP1 leads to reduced cell growth and increased differentiation. 156,157 In these cells, binding of EBP1 to ERBB3 is dependent on constitutive phosphorylation by PKC. 158 Upon NRG stimulation, EBP1 is phosphorylated, independent of PKC, dissociates from ERBB3, and translocates to the nucleus.…”

Section: Newly-identified Proteins Binding Erbb3 Phosphotyrosines-thementioning

confidence: 99%

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The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Newly-identified Proteins Binding Erbb3 Phosphotyrosines-thementioning

confidence: 99%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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“…Cell growth measurement in complete media was performed as described in ref. 23 by using a hemocytometer. For soft agar growth assays, increasing concentrations of cells (as indicated) were plated in 35-mm Petri dishes in 0.3% agar in complete media, and colonies were counted after 10 days of incubation (23).…”

Section: Methodsmentioning

confidence: 99%

“…23 by using a hemocytometer. For soft agar growth assays, increasing concentrations of cells (as indicated) were plated in 35-mm Petri dishes in 0.3% agar in complete media, and colonies were counted after 10 days of incubation (23). To assess the effect of dihydrotestosterone (DHT) on cell growth, cells (2 ϫ 10 4 ) were plated in 12-well plates in complete medium.…”

Section: Methodsmentioning

confidence: 99%

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

Zhang

Wang

Jelovac

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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101

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Down-regulation of the androgen receptor (AR) is being evaluatedas 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 ARregulated 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.ErbB receptors ͉ transcriptional corepressors ͉ androgen independence

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“…Ectopic expression of Ebp1 in ErbB-2, ErbB-3-expressing breast carcinoma cell lines resulted in inhibition of colony formation, a decreased proliferation rate, and suppression of growth in soft agar. Moreover, overexpression of Ebp1 led to a more differentiated phenotype in AU565 breast cancer cells (3). Epb1 has significant homology to the 38-kDa murine protein p38-2G4, which displays a cell-cycle-dependent expression pattern and binds to DNA (4).…”

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confidence: 99%

Ebp1 isoforms distinctively regulate cell survival and differentiation

Liu

Ahn

Liu

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

104

159

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Ebp1, an ErbB3 receptor-binding protein, inhibits the proliferation and induces the differentiation of human cancer cells. Ebp1 binds nuclear Akt and prevents DNA fragmentation by inhibiting caspaseactivated DNase. Here, we show that Ebp1 possesses two different isoforms, p48 and p42, which differentially mediate PC12 cell survival and differentiation. The longer-form p48 localizes in both the cytoplasm and the nucleus and suppresses apoptosis, whereas the shorter-form p42 predominantly resides in the cytoplasm and promotes cell differentiation. EGF strongly stimulates p42 to bind ErbB3, and the association depends on PKC-mediated phosphorylation of Ebp1. By contrast, p48 does not bind to ErbB3 regardless of EGF treatment. Overexpression of p48 provokes cell proliferation, which is inhibited by p42. Moreover, nerve growth factor elicits extensive sprouting in p42 stably transfected PC12 cells, whereas p48 cells reveal modest neurite outgrowth. Although mitogen-activated protein kinase cascade remains similar in both cells, Akt is more active in p48 cells than in p42 cells. Thus, Ebp1 might regulate cell survival and differentiation through two distinctive p48 and p42 isoforms.Akt ͉ cell death ͉ cell proliferation

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Ectopic expression of the ErbB-3 binding protein Ebp1 inhibits growth and induces differentiation of human breast cancer cell lines

Cited by 85 publications

References 30 publications

The ERBB3 receptor in cancer and cancer gene therapy

The ERBB3 receptor in cancer and cancer gene therapy

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

Ebp1 isoforms distinctively regulate cell survival and differentiation

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