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An expression signature of syndecan-1 (CD138), E-cadherin and c-met is associated with factors of angiogenesis and lymphangiogenesis in ductal breast carcinoma in situ.

Götte M, Kersting C, Radke I, Kiesel L, Wülfing P - Breast Cancer Res. (2007)

Bottom Line: E-cadherin expression decreased, and c-met expression increased progressively in more aggressive cell lines.E-cadherin expression was significantly associated with c-met and syndecan-1.Levels of c-met and syndecan-1 expression were associated with HER2 expression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Obstetrics and Gynecology, Münster University Hospital, Domagkstrasse 11, Münster, D-48149, Germany. mgotte@uni-muenster.de

ABSTRACT

Introduction: Heparan sulphate proteoglycan syndecan-1 modulates cell proliferation, adhesion, migration and angiogenesis. It is a coreceptor for the hepatocyte growth factor receptor c-met, and its coexpression with E-cadherin is synchronously regulated during epithelial-mesenchymal transition. In breast cancer, changes in the expression of syndecan-1, E-cadherin and c-met correlate with poor prognosis. In this study we evaluated whether coexpression of these functionally linked prognostic markers constitutes an expression signature in ductal carcinoma in situ (DCIS) of the breast that may promote cell proliferation and (lymph)angiogenesis.

Methods: Expression of syndecan-1, E-cadherin and c-met was detected immunohistochemically using a tissue microarray in tumour specimens from 200 DCIS patients. Results were correlated with the expression patterns of angiogenic and lymphangiogenic markers. Coexpression of the three prognostic markers was evaluated in human breast cancer cells by confocal immunofluorescence microscopy and RT-PCR.

Results: Coexpression and membrane colocalization of the three markers was confirmed in MCF-7 cells. E-cadherin expression decreased, and c-met expression increased progressively in more aggressive cell lines. Tissue microarray analysis revealed strong positive staining of tumour cells for syndecan-1 in 72%, E-cadherin in 67.8% and c-met in 48.6% of DCIS. E-cadherin expression was significantly associated with c-met and syndecan-1. Expression of c-met and syndecan-1 was significantly more frequent in the subgroup of patients with pure DCIS than in those with DCIS and a coexisting invasive carcinoma. Levels of c-met and syndecan-1 expression were associated with HER2 expression. Expression of c-met significantly correlated with expression of endothelin A and B receptors, vascular endothelial growth factor (VEGF)-A and fibroblast growth factor receptor-1, whereas E-cadherin expression correlated significantly with endothelin A receptor, VEGF-A and VEGF-C staining.

Conclusion: Syndecan-1, E-cadherin and c-met constitute a marker signature associated with angiogenic and lymphangiogenic factors in DCIS. This coexpression may reflect a state of parallel activation of different signal transduction pathways, promoting tumour cell proliferation and angiogenesis. Our findings have implications for future therapeutic approaches in terms of a multiple target approach, which may be useful early in breast cancer progression.

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RT-PCR analysis of Sdc1, E-cad and c-met in human breast cancer cell lines. RNA was prepared from MCF-7, MDA-MB468 and MDA-MB231 breast cancer cells; mRNA was reverse transcribed and used as a template for PCR amplification of Sdc1, E-cad and c-met (as described in Materials and methods section). (a) PCR band intensities were normalized for actin expression and the data from three independent experiments were analyzed using the paired Student's t-test. (b) *P < 0.01 (Sdc1: MDA-MB468 versus MDA-MB231; E-cad and c-met: MCF-7 versus MDA-MB231, MCF-7 versus MDA-MB468 and MDA-MB468 versus MDA-MB231). AU, arbitrary units; E-cad, E-cadherin; RT-PCR, reverse transcription polymerase chain reaction; Sdc, syndecan.
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Figure 2: RT-PCR analysis of Sdc1, E-cad and c-met in human breast cancer cell lines. RNA was prepared from MCF-7, MDA-MB468 and MDA-MB231 breast cancer cells; mRNA was reverse transcribed and used as a template for PCR amplification of Sdc1, E-cad and c-met (as described in Materials and methods section). (a) PCR band intensities were normalized for actin expression and the data from three independent experiments were analyzed using the paired Student's t-test. (b) *P < 0.01 (Sdc1: MDA-MB468 versus MDA-MB231; E-cad and c-met: MCF-7 versus MDA-MB231, MCF-7 versus MDA-MB468 and MDA-MB468 versus MDA-MB231). AU, arbitrary units; E-cad, E-cadherin; RT-PCR, reverse transcription polymerase chain reaction; Sdc, syndecan.

Mentions: We next compared expression of Sdc1, E-cad and c-met at the mRNA level by semiquantitative RT-PCR (Figure 2). Similar levels of Sdc1 expression were observed in MCF-7 and MDA-MB468 cells, but Sdc1 mRNA expression was significantly lower (P < 0.001) in MDA-MB231 cells than in MDA-MB468 cells. With increasing de-differentiation and higher metastatic potential (MCF-7 < MDA-MB468 < MDA-MB231), a significant decrease in E-cad mRNA expression was observed (Figure 2b). Of note, expression levels of c-met exhibited an inverse relation, with the highest expression in MDA-MB231 cells (Figure 2).


An expression signature of syndecan-1 (CD138), E-cadherin and c-met is associated with factors of angiogenesis and lymphangiogenesis in ductal breast carcinoma in situ.

Götte M, Kersting C, Radke I, Kiesel L, Wülfing P - Breast Cancer Res. (2007)

RT-PCR analysis of Sdc1, E-cad and c-met in human breast cancer cell lines. RNA was prepared from MCF-7, MDA-MB468 and MDA-MB231 breast cancer cells; mRNA was reverse transcribed and used as a template for PCR amplification of Sdc1, E-cad and c-met (as described in Materials and methods section). (a) PCR band intensities were normalized for actin expression and the data from three independent experiments were analyzed using the paired Student's t-test. (b) *P < 0.01 (Sdc1: MDA-MB468 versus MDA-MB231; E-cad and c-met: MCF-7 versus MDA-MB231, MCF-7 versus MDA-MB468 and MDA-MB468 versus MDA-MB231). AU, arbitrary units; E-cad, E-cadherin; RT-PCR, reverse transcription polymerase chain reaction; Sdc, syndecan.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1851383&req=5

Figure 2: RT-PCR analysis of Sdc1, E-cad and c-met in human breast cancer cell lines. RNA was prepared from MCF-7, MDA-MB468 and MDA-MB231 breast cancer cells; mRNA was reverse transcribed and used as a template for PCR amplification of Sdc1, E-cad and c-met (as described in Materials and methods section). (a) PCR band intensities were normalized for actin expression and the data from three independent experiments were analyzed using the paired Student's t-test. (b) *P < 0.01 (Sdc1: MDA-MB468 versus MDA-MB231; E-cad and c-met: MCF-7 versus MDA-MB231, MCF-7 versus MDA-MB468 and MDA-MB468 versus MDA-MB231). AU, arbitrary units; E-cad, E-cadherin; RT-PCR, reverse transcription polymerase chain reaction; Sdc, syndecan.
Mentions: We next compared expression of Sdc1, E-cad and c-met at the mRNA level by semiquantitative RT-PCR (Figure 2). Similar levels of Sdc1 expression were observed in MCF-7 and MDA-MB468 cells, but Sdc1 mRNA expression was significantly lower (P < 0.001) in MDA-MB231 cells than in MDA-MB468 cells. With increasing de-differentiation and higher metastatic potential (MCF-7 < MDA-MB468 < MDA-MB231), a significant decrease in E-cad mRNA expression was observed (Figure 2b). Of note, expression levels of c-met exhibited an inverse relation, with the highest expression in MDA-MB231 cells (Figure 2).

Bottom Line: E-cadherin expression decreased, and c-met expression increased progressively in more aggressive cell lines.E-cadherin expression was significantly associated with c-met and syndecan-1.Levels of c-met and syndecan-1 expression were associated with HER2 expression.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Obstetrics and Gynecology, Münster University Hospital, Domagkstrasse 11, Münster, D-48149, Germany. mgotte@uni-muenster.de

ABSTRACT

Introduction: Heparan sulphate proteoglycan syndecan-1 modulates cell proliferation, adhesion, migration and angiogenesis. It is a coreceptor for the hepatocyte growth factor receptor c-met, and its coexpression with E-cadherin is synchronously regulated during epithelial-mesenchymal transition. In breast cancer, changes in the expression of syndecan-1, E-cadherin and c-met correlate with poor prognosis. In this study we evaluated whether coexpression of these functionally linked prognostic markers constitutes an expression signature in ductal carcinoma in situ (DCIS) of the breast that may promote cell proliferation and (lymph)angiogenesis.

Methods: Expression of syndecan-1, E-cadherin and c-met was detected immunohistochemically using a tissue microarray in tumour specimens from 200 DCIS patients. Results were correlated with the expression patterns of angiogenic and lymphangiogenic markers. Coexpression of the three prognostic markers was evaluated in human breast cancer cells by confocal immunofluorescence microscopy and RT-PCR.

Results: Coexpression and membrane colocalization of the three markers was confirmed in MCF-7 cells. E-cadherin expression decreased, and c-met expression increased progressively in more aggressive cell lines. Tissue microarray analysis revealed strong positive staining of tumour cells for syndecan-1 in 72%, E-cadherin in 67.8% and c-met in 48.6% of DCIS. E-cadherin expression was significantly associated with c-met and syndecan-1. Expression of c-met and syndecan-1 was significantly more frequent in the subgroup of patients with pure DCIS than in those with DCIS and a coexisting invasive carcinoma. Levels of c-met and syndecan-1 expression were associated with HER2 expression. Expression of c-met significantly correlated with expression of endothelin A and B receptors, vascular endothelial growth factor (VEGF)-A and fibroblast growth factor receptor-1, whereas E-cadherin expression correlated significantly with endothelin A receptor, VEGF-A and VEGF-C staining.

Conclusion: Syndecan-1, E-cadherin and c-met constitute a marker signature associated with angiogenic and lymphangiogenic factors in DCIS. This coexpression may reflect a state of parallel activation of different signal transduction pathways, promoting tumour cell proliferation and angiogenesis. Our findings have implications for future therapeutic approaches in terms of a multiple target approach, which may be useful early in breast cancer progression.

Show MeSH
Related in: MedlinePlus