Tumour‐promoting activity of altered WWP1 expression in breast cancer and its utility as a prognostic indicator

Huu, Ngoc Sa Nguyen; Ryder, W. David J.; Zeps, Nikolajs; Flasza, Marzena; Chiu, Maybo; Hanby, Andrew M.; Poulsom, Richard; Clarke, Robert B.; Baron, Martín

doi:10.1002/path.2385

Cited by 36 publications

(55 citation statements)

References 30 publications

(49 reference statements)

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“…Three ER-positive cell lines with ErbB4 expression (BT474, MCF7 and HCC1500) also show higher levels of WWP1 compared with four ER-negative breast cancer cell lines (Figure 5e). The WWP1 protein expression has been associated with positive ER-a and good-prognosis breast tumors (Nguyen Huu et al, 2008;Chen et al, 2009). Consistently, most publications associated the ErbB4 protein expression with ER-a-positive, low grade and more differentiated breast tumors (Tang et al, 1999;Suo et al, 2001;Witton et al, 2003;Junttila et al, 2005).…”

Section: Discussionmentioning

confidence: 79%

“…Most studies suggest that ErbB4 also decreases breast epithelial cell proliferation (Pitfield et al, 2006;Muraoka-Cook et al, 2006a;Feng et al, 2007) and survival (Naresh et al, 2006;Vidal et al, 2007). As an ErbB4-negative regulator, WWP1 has been shown to promote breast epithelial cell proliferation and survival (Chen et al, 2007b(Chen et al, , 2009Nguyen Huu et al, 2008). Whether WWP1 regulates mammary gland development during pregnancy and lactation through suppressing ErbB4 in vivo remains to be elucidated by studying the breast-specific WWP1 knockout and WWP1 transgenic mice in the future.…”

Section: Discussionmentioning

confidence: 99%

“…The C-terminal HECT domain is the enzyme catalytic center for the ubiquitin transfer. WWP1 is overexpressed in prostate cancer (Chen et al, 2007a) and estrogen receptor-a (ER-a)-positive breast cancers and promotes breast cell proliferation and survival (Chen et al, 2007b(Chen et al, , 2009Nguyen Huu et al, 2008). WWP1 is an intrinsic E3 ubiquitin ligase for multiple PY motifs containing transcription factors, including Smad2 (Seo et al, 2004), RunX2 (Jones et al, 2006), KLF5 (Chen et al, 2005) and p63 (Li et al, 2008b).…”

Section: Introductionmentioning

confidence: 99%

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WW domain containing E3 ubiquitin protein ligase 1 targets the full-length ErbB4 for ubiquitin-mediated degradation in breast cancer

Zhou

Alimandi

et al. 2009

Oncogene

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ErbB4, a member of the epidermal growth factor receptor family, plays a role in normal breast and breast cancer development by regulating mammary epithelial cell proliferation, survival and differentiation. In this study, we show that WWP1, a C2-WW-HECT type E3 ubiquitin ligase, binds, ubiquitinates and destructs ErbB4-CYT1, but much less efficiently for CYT2, isoforms (both JMa and JMb). The protein-protein interaction occurs primarily between the first and third WW domains of WWP1 and the second PY motif of ErbB4. Knockdown of WWP1 by two different small interfering RNAs increases the endogenous ErbB4 protein levels in both MCF7 and T47D breast cancer cell lines. In addition, overexpression of the wild type, but not the catalytic inactive WWP1, dramatically decreases the endogenous ErbB4 protein levels in MCF7. Importantly, we found that WWP1 negatively regulates the heregulin-b1-stimulated ErbB4 activity as measured by the serum response element report assay and the BRCA1 mRNA expression. After a systematic screening of all WWP1 family members by small interfering RNA, we found that AIP4/Itch and HECW1/NEDL1 also negatively regulate the ErbB4 protein expression in T47D. Interestingly, the protein expression levels of both WWP1 and ErbB4 are higher in estrogen receptor-a-positive than in estrogen receptor-anegative breast cancer cell lines. These data suggest that WWP1 and its family members suppress the ErbB4 expression and function in breast cancer.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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WW domain containing E3 ubiquitin protein ligase 1 targets the full-length ErbB4 for ubiquitin-mediated degradation in breast cancer

Zhou

Alimandi

et al. 2009

Oncogene

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“…[23][24][25]33 Two other WWP1 family members, Itch and Nedd4, have been previously reported to target p63 proteins for proteasomal degradation. 24,25 However, the expression levels of Itch in breast cancer are not altered 34 although the expression of Nedd4 has been found to be overexpressed in invasive bladder cancer cells. 4 WWP1 is amplified and overexpressed in more than 30% of prostate and breast cancers, suggesting that WWP1 among these E3 ligases may have a major function for the p63 protein degradation in prostate and breast cancers, although we cannot completely exclude the roles of Itch and Nedd4.…”

Section: Discussionmentioning

confidence: 99%

WW domain-containing E3 ubiquitin protein ligase 1 targets p63 transcription factor for ubiquitin-mediated proteasomal degradation and regulates apoptosis

2008

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WWP1 E3 ubiquitin ligase has previously been shown to be frequently amplified and overexpressed in prostate and breast cancers. However, the mechanism of WWP1 action is still largely unknown. p63, a member of the p53 family of transcription factors, has an important function in tumor development by regulating apoptosis. Using alternative promoters, p63 can be expressed as DNp63 and TAp63. Increasing evidence suggests that TAp63 sensitizes cells to apoptosis but DNp63 has an opposite function. In this study, we show that WWP1 binds, ubiquitinates, and destructs both DNp63a and TAp63a. The proteinprotein interaction occurs between the PY motif of p63 and the WW domains of WWP1. The knockdown of WWP1 by siRNA increases the endogenous DNp63a level in the MCF10A and 184B5 immortalized breast epithelial cell lines and confers resistance to doxorubicin-induced apoptosis. On the other hand, the knockdown of WWP1 increases the endogenous level of TAp63a, induces apoptosis, and increases sensitivity to doxorubicin and cisplatin in the HCT116 colon cancer cell line in a p53-independent manner. Finally, we found that DNA damage chemotherapeutic drugs induce WWP1 mRNA and protein expression in a p53-dependent manner. These data suggest that WWP1 may have a context-dependent role in regulating cell survival through targeting different p63 proteins for degradation.

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“…20 Thus, WWP1 has the potential to become a useful clinical biomarker and a potential stand-alone prognostic factor. 21 The insulin-like growth factor 1 receptor (IGF-1R) is a tyrosine kinase growth factor receptor that has been linked to prognosis in a variety of malignancies. IGF-1R is a tetramer composed of 2 extracellular a subunits (130 KDa) and 2 transmembrane b subunits (90 KDa).…”

Section: Abstract: Wwp1; Breast Cancer; Ihc; Er; Igf-1rmentioning

confidence: 99%

Overexpression of WWP1 is associated with the estrogen receptor and insulin‐like growth factor receptor 1 in breast carcinoma

Chen

Zhou

Sheehan

et al. 2009

Intl Journal of Cancer

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WWP1, a HECT type E3 ubiquitin ligase frequently amplified and overexpressed in breast cancer, has the potential to become a useful clinical biomarker and therapeutic target in breast cancer. Here, we performed immunohistochemical staining in formalinfixed and paraffin-embedded tissue sections from 187 cases of primary invasive mammary carcinoma [137 ductal carcinomas (IDC) and 50 lobular carcinomas (ILC)] by using a monoclonal anti-WWP1 antibody. The normal breast epithelium and adjacent benign epithelium are essentially negative for WWP1. Cytoplasmic WWP1 immunoreactivity was observed in 76/187 (40.6%) tumors and showed a positive correlation with ERa (p 5 0.05) and IGF-1R proteins (p 5 0.001) in this cohort. The positive correlations between WWP1 and ER/IGF-1R were also observed in a panel of 12 breast cancer cell lines by Western blot. Interestingly, the ER levels are decreased when WWP1 is silenced in ER positive MCF7 and T47D breast cancer cell lines. Finally, WWP1 ablation collectively inhibits cell proliferation with tamoxifen in MCF7 and T47D, as measured by 3 H-thymidine incorporation assays. These findings suggest that WWP1 may play an important role in ER positive breast cancer. ' 2009 UICC

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Tumour‐promoting activity of altered WWP1 expression in breast cancer and its utility as a prognostic indicator

Cited by 36 publications

References 30 publications

WW domain containing E3 ubiquitin protein ligase 1 targets the full-length ErbB4 for ubiquitin-mediated degradation in breast cancer

WW domain containing E3 ubiquitin protein ligase 1 targets the full-length ErbB4 for ubiquitin-mediated degradation in breast cancer

WW domain-containing E3 ubiquitin protein ligase 1 targets p63 transcription factor for ubiquitin-mediated proteasomal degradation and regulates apoptosis

Overexpression of WWP1 is associated with the estrogen receptor and insulin‐like growth factor receptor 1 in breast carcinoma

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