Loss of EphB4 receptor tyrosine kinase protein expression during carcinogenesis of the human breast

Berclaz, Gilles; Flütsch, Bettina; Altermatt, Hans Jörg; Rohrbach, Valeria; Djonov, V.; Ziemiecki, Andrew; Dreher, E.; Andres, Anne‐Catherine

doi:10.3892/or.9.5.985

Cited by 43 publications

(54 citation statements)

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“…In human breast cancers, EphB4 has been reported to be elevated in primary infiltrating ductal breast carcinomas with a high grade of malignancy (5). In another report (6), however, EphB4 was negatively correlated with tumor growth. Interestingly, EphB4-positive cells were often found at the tumor borders and in regions that are rich in capillaries.…”

Section: S Everal Eph Receptors Are Overexpressed In Various Tumormentioning

confidence: 89%

Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth

Noren

Lu²,

Freeman³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

225

199

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Section: S Everal Eph Receptors Are Overexpressed In Various Tumormentioning

confidence: 89%

Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth

Noren

Lu²,

Freeman³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

225

199

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“…27 Interestingly, in a subsequent report, Berclaz et al 32 note a reduction in EphB4-positive cells on immunohistochemistry in breast carcinoma specimens compared to normal breast epithelium. These results contrast with their original report wherein strong expression of EphB4 transcripts was observed in the carcinomatous cells by in situ hybridization.…”

Section: Discussionmentioning

confidence: 99%

Receptor Tyrosine Kinase EphB4 Is a Survival Factor in Breast Cancer

Kumar

Singh

Xia

et al. 2006

The American Journal of Pathology

165

183

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EphB4, a member of the largest family of receptor tyrosine kinases, is normally expressed on endothelial and neuronal cells. Although aberrant expression of EphB4 has been reported in several human tumors, including breast cancer, its functional significance is not understood. We report here that EphB4 is expressed in 7 of 12 (58%) human breast cancer specimens and 4 of 4 (100%) breast tumor cell lines examined. Overexpression of EphB4 in breast cancer cells was driven by gene amplification and by the erbB family of receptors via activation of Janus tyrosine kinase-signal transducers and activators of transcription and protein kinase B. The aberrantly expressed receptor was phosphorylated by its natural ligand, EphrinB2, and signaled via the protein kinase B pathway. Targeted knockdown of EphB4 expression by small interference RNA (and antisense oligodeoxynucleotides (ODNs)) led to dose-dependent reduction in cell survival, increased apoptosis, and sensitization to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Antisense ODN-mediated EphB4 knockdown resulted in reduced tumor growth in a murine tumor xenograft model. Antisense ODNtreated tumors were 72% smaller than control tumors at 6 weeks, with an 86% reduction in proliferating cells, 15-fold increase in apoptosis, and 44% reduction in tumor microvasculature. Our data indicate that biologically active EphB4 functions as a survival factor in breast cancer and is a novel target for therapy. (Am J

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“…Downregulation of specific Eph members is exceptional in cancer, since many more examples document overexpression, which is sometimes related to cancer progression and prognosis of the patients. However, loss of Eph receptor expression has also been described in some tumors, for example, EphB4 in breast cancer 25 and EphB6 in metastatic melanoma. 26 In neuroblastoma, re-expression of EphB6 in tumor cells significantly suppressed their tumorigenicity.…”

Section: Epha1 In Skin Cancer C Hafner Et Almentioning

confidence: 99%

Expression profile of Eph receptors and ephrin ligands in human skin and downregulation of EphA1 in nonmelanoma skin cancer

et al. 2006

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Eph receptors and ephrin ligands represent the largest family of receptor tyrosine kinases. Beyond their welldefined meaning in developmental processes, these molecules also have important functions in adult human tissues and cancer. However, the Eph/ephrin expression profile in human skin is only marginally studied. We therefore investigated the mRNA expression of 21 Eph receptors and ephrin ligands in adult human skin in comparison to 13 other adult human tissues using quantitative real-time RT-PCR. In addition, immunohistochemistry was established for some members (EphA1, EphA2 and EphA7) to confirm the results of the RT-PCR and to identify the expressing cells in the skin. We found all investigated family members expressed in human skin, but at highly varying levels. EphA1, EphB3 and ephrin-A3 turned out to be most prominently expressed in skin compared to other adult human tissues. EphA1 was exclusively expressed in the epidermis. We therefore investigated the expression of EphA1 in nonmelanoma skin cancers derived from the epidermis (56 basal cell carcinomas and 32 squamous cell carcinomas). As demonstrated by immunohistochemistry, both skin cancers displayed a significant downregulation of EphA1 compared to the normal epidermis. In squamous cell carcinoma, the EphA1 downregulation was associated with increased tumor thickness, although this was not significant. Our results indicate that Eph receptors and ephrin ligands are widely expressed in the adult human skin, particularly in the epidermis, and may play an important role in skin homeostasis. EphA1 seems to be a marker of the differentiated normal epidermis and its downregulation in nonmelanoma skin cancer may contribute to carcinogenesis of these very frequent human tumors. EphA1 represents a new potential prognostic marker and therapeutic target in nonmelanoma skin cancer. Keywords: Eph receptor tyrosine kinase; ephrin; real-time RT-PCR; nonmelanoma skin cancer; EphA1; epidermis The Eph receptors represent the largest family of receptor tyrosine kinases. Eph receptors and their ephrin ligands are divided into the two subclasses A and B, based on the sequence homology of the extracellular sequence, the structure and the binding affinity.

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Loss of EphB4 receptor tyrosine kinase protein expression during carcinogenesis of the human breast

Cited by 43 publications

References 0 publications

Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth

Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth

Receptor Tyrosine Kinase EphB4 Is a Survival Factor in Breast Cancer

Expression profile of Eph receptors and ephrin ligands in human skin and downregulation of EphA1 in nonmelanoma skin cancer

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