Reduced E-Cadherin Expression is Associated With Invasiveness and Unfavorable Prognosis in Breast Cancer

Siitonen, Sanna; Kononen, Juha; Helin, Heikki; Rantala, Immo; Holli, Kaija; Isola, Jorma

doi:10.1093/ajcp/105.4.394

Cited by 262 publications

(235 citation statements)

References 20 publications

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“…E-cadherin is thought to act as a tumor suppressor gene in the breast, although the mechanism of E-cadherin-mediated tumor suppression has not been fully elucidated (17). Previous reports showed low expression of E-cadherin in breast cancers with increased invasiveness and high metastatic potential (13,14). Our results are in agreement with the literature in the sense that the non-IBC tumors with angiolymphatic invasion and/or metastases had significantly less E-cadherin expression than the tumors that did not have these features.…”

Section: Discussionsupporting

confidence: 92%

“…Diminished E-cadherin expression has been related to the acquisition of invasiveness in experimental tumors and in advanced-stage carcinomas, including ductal carcinomas of the breast (7)(8)(9)(10)(11)(12). Several studies have shown that E-cadherin expression is significantly reduced in high-grade, estrogen receptor (ER)-negative, and metastatic breast carcinomas (10,13,14). Loss of E-cadherin expression tends to appear in a heterogeneous pattern within carcinomas, suggesting that loss of expression of E-cadherin in these tumors is a potentially reversible somatic alteration.…”

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confidence: 99%

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Persistent E-Cadherin Expression in Inflammatory Breast Cancer

et al. 2001

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E-cadherin is a transmembrane glycoprotein that mediates epithelial cell-to-cell adhesion. Because loss of E-cadherin expression results in disruption of cellular clusters, it has been postulated that E-cadherin functions as a tumor suppressor protein. The role of E-cadherin in inflammatory breast cancer (IBC), a distinct and highly aggressive form of breast cancer, is largely unknown. The aim of our study was to elucidate whether E-cadherin expression contributes to the development and progression of the IBC phenotype and to investigate any differences in E-cadherin expression between IBC and stage-matched non-IBC. Forty-two breast cancer cases (20 IBC and 22 non-IBC) were identified. Strict and well-accepted criteria were used for the diagnosis of IBC. Clinical and pathologic features were studied, and formalin-fixed, paraffinembedded tissue sections were immunostained for E-cadherin, estrogen and progesterone receptors (ER and PR, respectively), and HER2/neu. Statistical analysis was performed using Fisher's exact test. All IBC uniformly expressed E-cadherin, whereas 15 of the 22 (68%) of the non-IBC expressed the protein (P ‫؍‬ .006). Intralymphatic tumor emboli in the IBC cases were also all E-cadherin positive. Two IBC tumors demonstrated invasive lobular histology, and both cases were positive for E-cadherin. Of the non-IBC cases, three were invasive lobular carcinomas, and all were positive for E-cadherin. No association was found between E-cadherin expression and ER, PR status, or HER2/neu overexpression. Our study demonstrates that there is a strong association between E-cadherin expression and IBC and suggests that E-cadherin may be involved in the pathogenesis of this form of advanced breast cancer. In our study, we demonstrate that circulating IBC tumor cells strongly express E-cadherin, thereby providing an important exception to the positive association between E-cadherin loss and poor prognosis in breast cancer. KEY WORDS: Breast cancer, E-cadherin, Inflammatory breast cancer, Metastasis, Tumor emboli. Mod Pathol 2001;14(5):458 -464Inflammatory breast cancer (IBC) accounts for approximately 6% of new breast cancers in the United States annually. It is the most aggressive and lethal form of locally advanced breast cancer, with a mean 5-year disease-free survival rate of Ͻ45% (1-3). IBC has unique clinical and pathological features. Clinically, patients present with skin erythema and nodularity; pathologically, IBC is highly angiogenic and angioinvasive, with numerous tumor emboli filling the dermal lymphatics. These tumor emboli are responsible for the striking clinical picture that arises from lymphatic obstruction (4 -6). E-cadherin is a transmembrane glycoprotein that mediates calcium-dependent intercellular adhesion and is specifically involved in epithelial cellto-cell adhesion (7). Diminished E-cadherin expression has been related to the acquisition of invasiveness in experimental tumors and in advanced-stage carcinomas, including ductal carcinomas of the breast (7-12). Several studies have ...

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Section: Discussionsupporting

confidence: 92%

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confidence: 99%

Persistent E-Cadherin Expression in Inflammatory Breast Cancer

et al. 2001

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“…Decreased E-cadherin expression is associated with a more aggressive behaviour of breast cancer (Siitonen et al, 1996). The homotypic cellular adhesion molecule E-cadherin is a transmembrane glycoprotein important for the organisation of epithelial structure (Takeichi, 1995;Huber et al, 1996;Yagi and Takeichi, 2000).…”

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confidence: 99%

E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines

et al. 2006

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Using genome-wide expression profiling of a panel of 27 human mammary cell lines with different mechanisms of E-cadherin inactivation, we evaluated the relationship between E-cadherin status and gene expression levels. Expression profiles of cell lines with E-cadherin (CDH1) promoter methylation were significantly different from those with CDH1 expression or, surprisingly, those with CDH1 truncating mutations. Furthermore, we found no significant differentially expressed genes between cell lines with wild-type and mutated CDH1. The expression profile complied with the fibroblastic morphology of the cell lines with promoter methylation, suggestive of epithelial -mesenchymal transition (EMT). All other lines, also the cases with CDH1 mutations, had epithelial features. Three non-tumorigenic mammary cell lines derived from normal breast epithelium also showed CDH1 promoter methylation, a fibroblastic phenotype and expression profile. We suggest that CDH1 promoter methylation, but not mutational inactivation, is part of an entire programme, resulting in EMT and increased invasiveness in breast cancer. The molecular events that are part of this programme can be inferred from the differentially expressed genes and include genes from the TGFb pathway, transcription factors involved in CDH1 regulation (i.e. ZFHX1B, SNAI2, but not SNAI1, TWIST), annexins, AP1/2 transcription factors and members of the actin and intermediate filament cytoskeleton organisation.

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“…Subsequent studies have shown loss of E-cadherin expression is a common ®nding in a wide spectrum of human epithelial cancers (Birchmeier and Behrens, 1994). In breast cancer, loss of E-cadherin expression has been correlated with a more invasive phentoype and a less di erentiated histology (Siitonen et al, 1996;Gamallo et al, 1993). Recent studies have provided more compelling evidence that E-cadherin inactivation does not simply re¯ect the cancer phenotype, but, in fact, Ecadherin inactivation has a causal role in the process.…”

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Extinction of E-cadherin expression in breast cancer via a dominant repression pathway acting on proximal promoter elements

1999

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Inactivation of the E-cadherin cell adhesion molecule is believed critical in the development and behavior of many epithelial cancers, though mutations in the E-cadherin gene account for inactivation in only a fraction of cases. In many breast cancer lines, E-cadherin transcription is extinguished, but the role and signi®cance of alterations in trans-acting transcription factors, promoter hypermethylation, and chromatin changes remain unresolved. To gain further insights into mechanisms underlying Ecadherin inactivation in breast cancer, we analysed somatic cell hybrids resulting from pairwise fusions between breast cancer lines with intact E-cadherin transcription (E-cad+) and lines lacking E-cadherin transcription (E-cad7). All hybrid lines failed to express E-cadherin transcripts and protein, despite the fact that E-cadherin alleles from E-cad+ lines were present in the hybrids. Elements in the proximal 108 bp of the Ecadherin promoter, when present in reporter gene constructs, were su cient to direct strong transcription in E-cad+ breast lines, but displayed weak activity in Ecad7 parental lines and hybrids. E-cadherin expression could not be restored in E-cad7 lines or hybrids by treatment with a DNA demethylating agent and/or a histone deacetylase inhibitor. Our ®ndings suggest loss of E-cadherin expression in some breast cancers may be due to dominant repression of the trans-acting pathways that regulate E-cadherin transcription.

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Reduced E-Cadherin Expression is Associated With Invasiveness and Unfavorable Prognosis in Breast Cancer

Cited by 262 publications

References 20 publications

Persistent E-Cadherin Expression in Inflammatory Breast Cancer

Persistent E-Cadherin Expression in Inflammatory Breast Cancer

E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines

Extinction of E-cadherin expression in breast cancer via a dominant repression pathway acting on proximal promoter elements

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