Estrogen receptor-α and C-ERBB-4 expression in breast carcinomas

Suo, Zhenhe; Berner, Heidi S.; Risberg, Bjørn; Karlsson, Mats G.; Nesland, Jahn M.

doi:10.1007/s004280000392

Cited by 29 publications

(21 citation statements)

References 44 publications

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“…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). However, knockdown of endogenous WWP1 significantly upregulates endogenous ErbB4 protein expression in both T47D and MCF7 (Figure 4a).…”

Section: Discussionsupporting

confidence: 57%

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: Discussionsupporting

confidence: 57%

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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“…Most studies presented to date do not have congruent findings regarding the prognostic effect of c-erbB-4 in breast cancer. Some studies linked c-erbB4 overexpression with a well-differentiated phenotype (Kew et al, 2000;Suo et al, 2002), positive ER status (Knowlden et al, 1998;Suo et al, 2001) and longer survival (Suo et al, 2002;Witton et al, 2003). Another study associated overexpression with poor survival in lymph node-positive cases (Lodge et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Significant correlations have been found between c-erbB-3 overexpression and tumour size (Travis et al, 1996) and histological grade (Naidu et al, 1998). Studies on c-erbB-4 expression have shown an association with well-differentiated tumours (Kew et al, 2000;Suo et al, 2002) and positive ER status (Suo et al, 2001). Some studies have found an association with better survival (Pawlowski et al, 2000;Suo et al, 2002), while others have reported an association with poor survival (Lodge et al, 2003) or no association with survival (Kew et al, 2000).…”

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confidence: 99%

Expression and co-expression of the members of the epidermal growth factor receptor (EGFR) family in invasive breast carcinoma

et al. 2004

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The epidermal growth factor receptor (EGFR) family plays an important role in breast carcinogenesis. Much interest has been focused recently on its members because of their potential role as prognostic indicators in breast cancer and their involvement in cancer therapy. We have evaluated more than 1500 cases of invasive breast carcinoma immunohistochemically using tissue microarray technology to examine the expression of EGFR family receptor proteins. We have found that 20.1 and 31.8% of cases were positive for EGFR and c-erbB-2, respectively, and 45 and 45.1% of tumours overexpressed for c-erbB-3 and c-erbB-4, respectively. The expression of either EGFR or c-erbB-2 was associated with other bad prognostic features and with poor outcome. Neither c-erbB-3 nor c-erbB-4 had any association with survival. c-erbB-2 had an independent prognostic effect on overall and disease-free survival (DFS) in all cases, as well as in the subset of breast carcinoma patients with nodal metastases. Several hetero-and homodimeric combinations have been reported between the EGFR members. Those dimers can evoke diverse signal transduction pathways with variable cellular responses. We stratified cases according to their co-expression of receptors into distinct groups with different receptor-positive combinations. Patients whose tumours co-expressed c-erbB-2 and c-erbB-3, as well as those whose tumours coexpressed EGFR, c-erbB-2 and c-erbB-4 showed an unfavourable outcome compared with other groups, while combined c-erbB-3 and c-erbB-4 expression was associated with a better outcome. In cases showing expression of one family member only (homodimers), we found a significant association between c-erbB-4 homodimer-expressing tumours and better DFS. In contrast, patients with c-erbB-2 homodimer-expressing tumours had a significant poorer DFS compared with other cases. These data imply that the combined profile expression patterns of the four receptor family members together provide more accurate information on the tumour behaviour than studying the expression of each receptor individually.

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“…Thus the role of nuclear 4ICD shifts from a benign STAT5A coactivator driving differentiation in the normal breast to an ERα coactivator promoting breast tumor proliferation. There is a strong selection for the ERα/4ICD signaling axis in developing tumors with several studies reporting between 74-91% of low grade ERα(+) tumors coexpressing HER4 [43,45,61]. Clinically this combination of ERα expression and nuclear accumulation of the 4ICD/ERα transcriptional complex predicts worse patient prognosis than the combination of ERα and membrane associated HER4 [20,28] providing strong clinical support for a ERα/4ICD tumor cell proliferation signal.…”

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confidence: 99%

HER4 Intracellular Domain (4ICD) Activity in the Developing Mammary Gland and Breast Cancer

Jones

2008

J Mammary Gland Biol Neoplasia

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The HER4 receptor tyrosine kinase was the final member of the EGFR-family to be discovered. In contrast to the other three members of this receptor family which function primarily as mitogenic effectors in the breast, HER4 appears to have multiple divergent functions in the normal and malignant breast. Interestingly, the majority of HER4 activities in the breast including pregnancy induced differentiation and lactation initiation, transcriptional activation, tumor cell proliferation, growth suppression, and induction of apoptosis appear to be mediated by an independently signaling soluble HER4 intracellular domain (4ICD). The 4ICD can accumulate within the nucleus or mitochondria and subcellular localization of 4ICD in part determines the physiological response of breast cells to 4ICD action. Here I will discuss the evidence supporting the role of 4ICD as the critical effector of HER4 signaling in the breast. In addition a developmental and temporal model of 4ICD action in the normal breast and during the progression of breast cancer will be presented to explain the paradox of divergent HER4 and 4ICD activities. KeywordsEGFR-family; Estrogen receptor; BCL-2 family; Apoptosis; Transcription Proteolytic Processing of HER4 to Generate a Soluble HER4 Intracellular Domain (4ICD)It is well accepted that the HER4 transmembrane receptor undergoes regulated intramembrane proteolysis (RIP) at the cell surface to release a soluble intracellular domain (ICD); a property that remains unique among EGFR-family members. An excellent review of the molecular details underlying HER4 RIP was recently published elsewhere [1]. In summary, ectodomain cleavage of the 180 kDa HER4 cell surface receptor is mediated by tumor necrosis factor α converting enzyme (TACE), a member of the ADAM metalloproteinase family referred to as ADAM17 [2]. Following TACE cleavage the ca. 120 kDa HER4 ectodomain, which includes the ligand binding region, is shed into the extracellular milieu while the remaining 80 kDa cleavage product (m80) is retained as a transmembrane peptide. The m80 harbors an active tyrosine kinase [3] and a carboxyl terminus with several potential tyrosine phosphorylation sites. Although the m80 is phosphorylated it remains unclear if this membrane tethered peptide transmits cellular signals. The HER4 m80 however is a substrate for presenilin-dependentsecretase cleavage. This RIP event results in membrane release of a soluble 4ICD. Depending upon specific cellular properties, that we are beginning to understand, membrane released 4ICD may translocate to the nucleus or remain in the cytosol where mitochondrial accumulation has e-mail: fjones@tulane.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript been observed (Fig. 1). The 4ICD is emerging as a unique independently signaling molecule and the impact of 4ICD signaling in the breast will be discussed in detail here. [16][17][18]. Although there is increasing evidence to suggest that phosphorylation of γ-secretase and its substra...

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Estrogen receptor-α and C-ERBB-4 expression in breast carcinomas

Cited by 29 publications

References 44 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

Expression and co-expression of the members of the epidermal growth factor receptor (EGFR) family in invasive breast carcinoma

HER4 Intracellular Domain (4ICD) Activity in the Developing Mammary Gland and Breast Cancer

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