Estrogen-Responsive Finger Protein as a New Potential Biomarker for Breast Cancer

Suzuki, Takashi; Urano, Tomohiko; Tsukui, Tohru; Horie‐Inoue, Kuniko; Moriya, Takuya; Ishida, Toru; Muramatsu, Masami; Ouchi, Yasuyoshi; Sasano, Hironobu; Inoue, Satoshi

doi:10.1158/1078-0432.ccr-05-0040

Cited by 64 publications

(48 citation statements)

References 20 publications

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“…In some cases, this upregulation was associated with enhanced metastatic capacity as well as with poor patient prognosis (Bektas et al, 2008) In contrast, Ube1L is often lost or downregulated in lung cancer, indicating a tumorsuppressor function of Ube1L in this tissue (Pitterle et al, 1998). The EFP expression is increased in advanced breast tumors and positively correlates with a poor prognosis (Sakuma et al, 2005;Suzuki et al, 2005), which seems to be tightly connected to the specific function of EFP in the regulation of ER activity. As these distinct dysregulated expression patterns of the ISGylation system may reflect the tissue-specific functions of the components, an upregulation of ISG15, UbcH8, EFP and Herc5 in PCa is probably associated with a tissue-specific function of the ISGylation system in AR regulation.…”

Section: Discussionmentioning

confidence: 95%

Expression, regulation and function of the ISGylation system in prostate cancer

et al. 2009

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The androgen receptor (AR) plays a crucial role in the modulation of prostate cell proliferation and is involved in the development and progression of prostate cancer (PCa). An understanding of the complex regulation of AR provides novel treatment options for PCa. Here, we show (i) that the ubiquitin-like modifier, interferon-stimulated gene 15 (ISG15), and most enzymes involved in ISG15 conjugation were upregulated in tumor samples versus in non-malignant tissues of PCa patients and (ii) that the expression of these components significantly differed between tumors in patients treated with and without androgen ablation. Using PCa cell lines as in vitro models, the specific androgen-mediated, ARdependent regulation of the ISGylation components was confirmed. In addition, the ISGylation system controls AR mRNA and protein expressions, as overexpression of Ube1L as a limiting ISGylation factor in the AR þ androgensensitive PCa cell line, LNCaP, results in significant AR upregulation, accompanied by an increased proliferation even under androgen deprivation. Accordingly, Ube1L knockdown decreased the AR expression. Thus, this study describes for the first time the modulation of AR expression by ISGylation components, which affects the proliferation of PCa cells, thereby providing evidence for a novel function of the ISGylation system in malignant transformation.

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Section: Discussionmentioning

confidence: 95%

Expression, regulation and function of the ISGylation system in prostate cancer

et al. 2009

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“…9 EFP mRNA and protein were reported to be overexpressed and significantly correlated with poor prognosis of breast cancer patients. 10 WW domain-containing protein 1 (WWP1) is an HECT (homologous to the E6-associated protein carboxyl terminus) domain-containing E3 ubiquitin ligase. Growing evidence suggests that WWP1 negatively regulates the TGF-b tumor suppressor pathway by mediating the ubiquitination and degradation of TGFb receptor 1 (TbR1), 11 Smad2 12 and Smad4.…”

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confidence: 99%

The amplified WWP1 gene is a potential molecular target in breast cancer

Chen

Zhou

Ross

et al. 2007

Intl Journal of Cancer

128

136

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The amplification of the q21 band of chromosome 8 (8q21) occurs in a large percentage of breast cancers. WWP1, an HECT domain-containing ubiquitin E3 ligase located in the 8q21 region, negatively regulates the TGF-b tumor suppressor pathway. To characterize the role of WWP1 in breast cancer, we analyzed WWP1 gene dosage and expression level as well as WWP1's function. A copy number gain of WWP1 was found in 51% (18/35) of breast cancer cell lines and in 41% (17/41) of primary breast tumors. Expression of WWP1 mRNA was analyzed with real-time RT-PCR, Northern blot, and Western blot. WWP1 mRNA is upregulated in 58% (19/33) of breast cancer cell lines, and overexpression of WWP1 is significantly correlated with a gene copy number gain. In a panel of cDNA from primary breast tumors and normal tissues, expression of WWP1 in tumors is significantly higher than that in normal tissues. Functionally, RNAi-mediated WWP1 knockdown significantly induced cell growth arrest and apoptosis in the MCF7 and HCC1500 breast cancer cell lines. Consistently, WWP1 inhibition activated caspases. Forced overexpression of WWP1 by the lentiviral system in 2 immortalized breast epithelial cell lines MCF10A and 184B5 promoted cell proliferation. These results suggest that genomic aberrations of WWP1 may contribute to the pathogenesis of breast cancer. ' 2007 Wiley-Liss, Inc.Key words: WWP1; breast cancer; gene amplification; overexpression; apoptosis A copy number gain or loss is a frequent genetic alteration in solid tumors including breast cancer. A copy number gain of 8q21 was detected in a high percentage of familial and sporadic breast tumors.1-3 Although several 8q21 genes, such as TPD52 and E2F5, have been reported to be amplified and overexpressed in breast cancer, 4,5 their roles have not been firmly established in breast tumorigenesis, and the underlying target genes of 8q21 amplification in breast cancer remain to be elucidated.Ubiquitin proteasome pathway (UPP)-mediated protein degradation plays an important role in breast cancer cell proliferation, apoptosis and carcinogenesis.6 Several oncogenic ubiquitin E3 ligases have been identified as diagnosis markers or potential drug targets in human breast cancer.7 For example, Skp2, an F-box protein in the SCF ubiquitin ligase complex, targets the CDK inhibitor p27 kip for degradation and is overexpressed in a subset of breast carcinomas. 8 The ring finger E3 ligase EFP mediates estrogen-induced cell growth and facilitates 14-3-3r tumor suppressor ubiquitination and proteolysis.9 EFP mRNA and protein were reported to be overexpressed and significantly correlated with poor prognosis of breast cancer patients. 10WW domain-containing protein 1 (WWP1) is an HECT (homologous to the E6-associated protein carboxyl terminus) domain-containing E3 ubiquitin ligase. Growing evidence suggests that WWP1 negatively regulates the TGF-b tumor suppressor pathway by mediating the ubiquitination and degradation of TGFb receptor 1 (TbR1), In our previous study, we found that WWP1 is amplified and overe...

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“…Further, Efp has been identified as an independent prognostic factor for breast cancer, regardless of ERa status. 7 Therefore, we expect that if Efp is expressed, siEfp-1 and chimeric siEfp will be used as new therapeutic tools for breast cancer treatment regardless of ERa status and can be used to treat patients with endocrine-resistant or relapsed tumors.…”

Section: Discussionmentioning

confidence: 99%

“…4 Clinicopathological studies on breast cancer patients have revealed that Efp immunoreactivity was positively associated with the lymph node status or ERa status and negatively correlated with histological grade. 7 Multivariate analyses of disease-free survival and overall survival of breast cancer patients have revealed that Efp immunoreactivity is correlated with poor prognosis and is an independent marker of breast cancer. 7 Moreover, we showed that Efp promotes the growth of breast tumors by functioning as a ubiquitin E3 ligase that targets the G2/M cell-cycle checkpoint 14-3-3s.…”

Section: Introductionmentioning

confidence: 99%

“…7 Multivariate analyses of disease-free survival and overall survival of breast cancer patients have revealed that Efp immunoreactivity is correlated with poor prognosis and is an independent marker of breast cancer. 7 Moreover, we showed that Efp promotes the growth of breast tumors by functioning as a ubiquitin E3 ligase that targets the G2/M cell-cycle checkpoint 14-3-3s. 8 Therefore, Efp is considered to be a factor essential in estrogen-dependent cancer proliferation and is a new target of breast cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

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Knockdown of Efp by DNA-modified small interfering RNA inhibits breast cancer cell proliferation and in vivo tumor growth

et al. 2010

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The estrogen-responsive gene Efp promotes the growth of breast cancer cells by stimulating the degradation of a negative cell-cycle regulator, 14-3-3s, and is hence considered a suitable molecular target for breast cancer therapy. The use of small interfering RNA (siRNA) and its derivatives to silence cancer-related genes is being investigated with the aim of identifying clinical applications for these molecules. Recently, it has been shown that DNA-modified siRNA (chimeric siRNA) has good potential in clinical applications, because it induces fewer off-target effects or immune responses in mammalian cells. In the present study, we identified the most specific and effective siRNA (siEfp-1) for silencing Efp expression in MCF-7 breast cancer cells. For this purpose, we used an algorithm that primarily eliminates off-target effects. siEfp-1 considerably suppressed the in vitro proliferation and cell-cycle progression of MCF-7 cells, as well as the in vivo growth of MCF-7 tumors, in athymic mice. DNA-modified siEfp-1 (chimeric siEfp) significantly inhibited the expression of Efp, proliferation of cultured cells and the in vivo growth of MCF-7-derived tumors in athymic mice. In addition, the silencing of Efp expression by siEfp-1 and chimeric siEfp increased the expression of the 14-3-3s protein. These results suggest that siEfp-1 and chimeric siEfp could be useful in breast cancer therapy. Chimeric siEfp, in particular, has a high specificity and induces few side effects and is therefore expected to be used as a novel nucleic acid-based therapeutic agent.

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Estrogen-Responsive Finger Protein as a New Potential Biomarker for Breast Cancer

Cited by 64 publications

References 20 publications

Expression, regulation and function of the ISGylation system in prostate cancer

Expression, regulation and function of the ISGylation system in prostate cancer

The amplified WWP1 gene is a potential molecular target in breast cancer

Knockdown of Efp by DNA-modified small interfering RNA inhibits breast cancer cell proliferation and in vivo tumor growth

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