E-cadherin as a prognostic indicator in primary breast cancer

Parker, Catriona; Rampaul, R.S.; Pinder, Sarah; Bell, Jane M.; Wencyk, P.M.; Blamey, R.W.; Nicholson, Robert Ian; Robertson, J. F. R.

doi:10.1054/bjoc.2001.2178

Cited by 67 publications

(69 citation statements)

References 22 publications

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“…Furthermore, node-negative and nodepositive tumours exhibited similar E-cadherin expression and no correlation between E-cadherin expression and metastatic status was observed. A number of additional reports show similar results regarding E-cadherin expression and tumour aggressiveness, implying that invasion is not necessarily dependent on a complete transition to a mesenchymal phenotype (Parker et al, 2001;Kovacs et al, 2003). Barrallo-Gimeno and co-workers argued that the primary function of Snail is to enhance cell movement, rather than to induce EMT (Barrallo-Gimeno and Nieto, 2005).…”

Section: Discussionmentioning

confidence: 75%

Hypoxia, Snail and incomplete epithelial–mesenchymal transition in breast cancer

2009

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BACKGROUND: Hypoxia is an element of the tumour microenvironment that impacts upon numerous cellular factors linked to clinical aggressiveness in cancer. One such factor, Snail, a master regulator of the epithelial -mesenchymal transition (EMT), has been implicated in key tumour biological processes such as invasion and metastasis. In this study we set out to investigate regulation of EMT in hypoxia, and the importance of Snail in cell migration and clinical outcome in breast cancer. METHODS: Four breast cancer cell lines were exposed to 0.1% oxygen and expression of EMT markers was monitored. The migratory ability was analysed following Snail overexpression and silencing. Snail expression was assessed in 500 tumour samples from premenopausal breast cancer patients, randomised to either 2 years of tamoxifen or no adjuvant treatment. RESULTS: Exposure to 0.1% oxygen resulted in elevated levels of Snail protein, along with changes in vimentin and E-cadherin expression, and in addition increased migration of MDA-MB-468 cells. Overexpression of Snail increased the motility of MCF-7, T-47D and MDA-MB-231 cells, whereas silencing of the protein resulted in decreased migratory propensity of MCF-7, MDA-MB-468 and MDA-MB-231 cells. Moreover, nuclear Snail expression was associated with tumours of higher grade and proliferation rate, but not with disease recurrence. Interestingly, Snail negativity was associated with impaired tamoxifen response (P ¼ 0.048). CONCLUSIONS: Our results demonstrate that hypoxia induces Snail expression but generally not a migratory phenotype, suggesting that hypoxic cells are only partially pushed towards EMT. Furthermore, our study supports the link between Snail and clinically relevant features and treatment response.

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Section: Discussionmentioning

confidence: 75%

Hypoxia, Snail and incomplete epithelial–mesenchymal transition in breast cancer

2009

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“…39,40 In ductal carcinomas of the breast, immunohistochemical studies have not demonstrated any apparent correlation of E-cadherin expression with the scattered morphology, tumor type, nodal status, disease recurrence, distant metastases, or other prognostic factors. [41][42][43][44] These observations suggest that a complete transition to a mesenchymal phenotype associated with transcriptional switching is not required for increased malignancy. Most advanced carcinomas may display some mesenchymal features but still retain well-differentiated epithelial cell characteristics.…”

Section: Discussionmentioning

confidence: 92%

Tenascin C Induces Epithelial-Mesenchymal Transition–Like Change Accompanied by SRC Activation and Focal Adhesion Kinase Phosphorylation in Human Breast Cancer Cells

Nagaharu

Zhang

Yoshida

et al. 2011

The American Journal of Pathology

119

110

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Tenascin C (TNC) is an extracellular matrix glycoprotein up-regulated in solid tumors. Higher TNC expression is shown in invading fronts of breast cancer, which correlates with poorer patient outcome. We examined whether TNC induces epithelial-mesenchymal transition (EMT) in breast cancer. Immunohistochemical analysis of invasive ductal carcinomas showed that TNC deposition was frequent in stroma with scattered cancer cells in peripheral margins of tumors. The addition of TNC to the medium of the MCF-7 breast cancer cells caused EMT-like change and delocalization of E-cadherin and ␤-catenin from cell-cell contact. Although amounts of E-cadherin and ␤-catenin were not changed after EMT in total lysates, they were increased in the Triton X-100-soluble fractions, indicating movement from the membrane into the cytosol. In wound healing assay, cells were scattered from wound edges and showed faster migration after TNC treatment. The EMT phenotype was correlated with SRC activation through phosphorylation at Y418 and phosphorylation of focal adhesion kinase ( Epithelial cells are polarized and tightly interconnected by cellular junctions, whereas mesenchymal cells never form stable intercellular contacts in adult tissues. Epithelial-mesenchymal transition (EMT) is a process whereby polarized epithelial cells are converted into mesenchymal cells during embryogenesis and in diseased tissues. 1-4 EMT events also take place during tumor progression in association with invasion and metastasis, when carcinoma cells stably or transiently lose their epithelial polarity and intercellular connections, allowing them to escape the surrounding epithelium and acquire higher locomotive behavior like mesenchymal cells. 2,[5][6][7][8] Many recent studies have demonstrated that EMT is controlled by complex signaling pathways initiated from tyrosine-receptor kinases, transforming growth factor-␤ (TGF-␤) receptors, Wnt pathways, Notch pathways, and integrins, which are triggered by various extracellular signals. 2,4,9 The activated pathways, including RAS/ mitogen-activated protein kinase, phosphoinositol 3 kinase, SRC, and focal adhesion kinase (FAK), also induce cytoskeletal reorganization, causing dissociation of E-cadherin from the membrane, loss of epithelial morphology, and increased cell motility. 2,4,9,10 Expression of transcriptional regulators such as SNAI1/2 and TWIST, followed by transcriptional switching from epithelial markers to mesenchymal ones, also has been reported. 2,11,12

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“…Tumors, all with neoplastic cellularity greater than 50%, were obtained with appropriate ethical approval and are detailed in Supplementary Tables 2 and 3. The breast tumors were primary operable invasive breast cancers from the Nottingham City Hospital Tumor Bank (Elston and Ellis, 1991;Parker et al, 2001;Miremadi et al, 2002). Ovarian tumors were from Addenbrooke's Hospital, Cambridge.…”

Section: Primary Tumors and Cell Linesmentioning

confidence: 99%

A 1 Mb minimal amplicon at 8p11–12 in breast cancer identifies new candidate oncogenes

et al. 2005

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Amplification of 8p11-12 is a well-known alteration in human breast cancers but the driving oncogene has not been identified. We have developed a high-resolution comparative genomic hybridization array covering 8p11-12 and analysed 33 primary breast tumors, 20 primary ovarian tumors and 27 breast cancer cell lines. Expression analysis of the genes in the region was carried out by using real-time quantitative PCR and/or oligo-microarray profiling. In all, 24% (8/33) of the breast tumors, 5% (1/20) of the ovary tumors and 15% (4/27) of the cell lines showed 8p11-12 amplification. We identified a 1 Mb segment of common amplification that excludes previously proposed candidate genes. Some of the amplified genes did not show overexpression, whereas for others, overexpression was not specifically attributable to amplification. The genes FLJ14299, C8orf2, BRF2 and RAB11FIP, map within the 8p11-12 minimal amplicon, two have a putative function consistent with an oncogenic role, these four genes showed a strong correlation between amplification and overexpression and are therefore the best candidate driver oncogenes at 8p12.

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E-cadherin as a prognostic indicator in primary breast cancer

Cited by 67 publications

References 22 publications

Hypoxia, Snail and incomplete epithelial–mesenchymal transition in breast cancer

Hypoxia, Snail and incomplete epithelial–mesenchymal transition in breast cancer

Tenascin C Induces Epithelial-Mesenchymal Transition–Like Change Accompanied by SRC Activation and Focal Adhesion Kinase Phosphorylation in Human Breast Cancer Cells

A 1 Mb minimal amplicon at 8p11–12 in breast cancer identifies new candidate oncogenes

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