ADAM17 gene expression in laser-capture microdissected breast cancers


ADAM17 gene expression in laser-capture microdissected breast cancers

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Title: ADAM17 gene expression in laser-capture microdissected breast cancers
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Article_Title: ADAM17 gene expression in laser-capture microdissected breast cancers
Authors: Diana Narita1*, Edward Seclaman1, Razvan Ilina1, Natalia Cireap1, George Ciprian Pribac2, Aurel Ardelean2, Tiberiu Nicola1, Andrei Anghel1
Affiliation: 1 University of Medicine and Pharmacy “Victor Babes”, Timisoara, Romania
2 “Vasile Goldis” Western University, Institute of Life Sciences, Arad, Romania
Abstract: Background. ADAMS (a desintegrin and metalloprotease) are transmembrane multifunctional glycoproteins, involved in cell growth, differentiation, motility, cell signaling and respectively, tumor growth, progression and spread. Our aim was to evaluate ADAM17 gene expression in homogenous, laser-capture microdissected breast cancers and to correlate their level of expression with cancers clinical and pathological characteristics. Materials and Methods. Expression of ADAM17 was analyzed using quantitative reverse-transcription polymerase chain reaction in laser-capture microdissected breast cancers specimens and corresponding non-neoplastic breast tissues from 38 patients. Results. We measured significantly elevated amounts of ADAM17 transcripts in malignant breast cells compared with normal adjacent breast tissue. Increased expression of ADAM17 showed high-grade cancers (p=0.04), but any significant differences were found related to age, stage, histology, tumor size, nodal, and ER/PR status; although not statistically significant, increased ADAM17 expressions showed HER2/neu positive, highly proliferative (high Ki67) and metastasized cancers. Conclusions. Our study provides further evidence of ADAM17 up-regulations in breast cancers and confers further motivation for future work on development of ADAM-selective inhibitors for cancers treatment.
Keywords: ADAM17, gene expression, laser-capture microdissection, breast cancers
References: Blobel CP. ADAMS: key components in EGFR signalling and development. Nat Rev Cancer, 6:32-43, 2005.
Arribas J, Bech-Serra JJ, Santiago-Josefat B ADAMs, cell migration and cancer. Cancer Metastasis Rev 25:57–68, 2006.
Ohtsu H, Dempsey PJ, Eguchi S ADAMs as mediators of EGF receptor transactivation by G-protein-coupled receptors. Am J Physiol Cell Physiol 291:C1–10, 2006
Mochizuki A, Okada Y ADAMs in cancer cell proliferation and progression. Cancer Sci 98:621-628, 2007.
Murphy G The ADAMs: signalling scissors in the tumor microenvironment. Nature Reviews Cancer, 8:929-941, 2008
Edwards DR, Handsley MM, Pennington CJ The ADAM metalloproteinases. Mol Aspects Med 29:258–289, 2008.
Duffy MJ, McKiernan E, O’Donovan N, McGowan P. Role of ADAMs in Cancer Formation and Progression. Clin Cancer Res 15:1140-1144, 2009.
McGowan PM, McKiernan E, Bolster F, et al. ADAM-17 predicts adverse outcome in patients with breast cancer. Ann Oncol 19:1075-1081, 2008.
Minn AJ, Kang Y, Serganova I,Gupta GP, Giri DD, Doubrovin M, Ponomarev V, Gerald WL, Blasberg R, Massagué J. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors.J Clin Invest, 115, 44-55, 2005.
Borrell-Pages M, Rojo F, Albanell J, Baselga J, Arribas J. TACE is required for the activation of the EGFR by TGF-alpha in tumors. EMBO J 22:1114–1124, 2003.
Zheng Y, Saftig P, Hartmann D, Blobel C. Evaluation of the contribution of different ADAMs to tumor necrosis factor α (TNF α) shedding and of the function of the TNF α ectodomain in ensuring selective stimulated shedding by the TNF α convertase (TACE/ADAM17). J Biol Chem 41:42898-42906, 2004.
Zucker S, Cao J, Chen WT. Critical appraisal of the use of matrix metalloproteinases inhibitors in cancer treatment. Oncogene 19:6642–6650, 2000.
Zhou BB, Petyon M, He B, et al. Targeting ADAM-mediated ligand cleavage toinhibit HER2 and EGFR pathways in non-small cell lung cancer. Cancer Cell 10:39–50, 2006.
Liu X, Fridman JS, Wang Q et al. Selective inhibition of ADAM metalloproteases blocks HER-2 extracellular domain (ECD) cleavage and potentiates the anti-tumor effects of trastuzumab. Cancer Biol Ther 5:648–656, 2006.
Fridman JS, Caulder E, Hansbury M. Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer. Clin Cancer Res 13:1892–1902, 2007.
De Kok JB, Roelofs RW, Giesendorf BA et al. Normalization of gene expression measurements in tumor tissues: comparison of 13 endogenous control genes. Lab Invest 85:154-159, 2005.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods 25:402-408, 2000.
Iba K, Albrechtsen R, Gilpin B, Fröhlich C, et al. The cysteine-rich domain of human ADAM 12 supports cell adhesion through syndecans and triggers signaling events that lead to β1 integrin-dependent cell spreading. J Cell Biol 149:1143–56, 2000.
Atfi A, Dumont E, Colland F, et al. The disintegrin and metalloproteinase ADAM12 contributes to TGF-β signaling through interaction with the type II receptor. J Cell Biol 178:201–208, 2007.
Dyczynska E, Syta E, Sun D, Zolkiewska A Breast cancer-associated mutations in metalloprotease disintegrin ADAM12 interfere with the intracellular trafficking and processing of the protein. Int J Cancer 122:2634-2640, 2008.
Le Pabic H, Bonnier D, Wewer UM, et al. ADAM12 in human liver cancers: TGF-β-regulated expression in stellate cells is associated with matrix remodeling. Hepatology 37:1056–1066, 2003.
Pories S, Zurakowski D, Roy R, et al. Urinary metalloproteinases: noninvasive biomarkers for breast cancer risk assessment. Cancer Epidemiol Biomarkers Prev, 17:1034-1042, 2008.
Shi Z, Xu W, Loechel F, Wewer UM, Murphy LJ. ADAM12, a disintegrin and metalloprotease, interacts with insulin-like growth factor-binding protein-3. J Biol Chem 275:18 574–18 580, 2000.
Laigaard J, Sørensen T, Fröhlich C, et al. ADAM12: a novel first-trimester maternal serum marker for Down syndrome. Prenat Diagn 23:1086–1091, 2003.
Roy R, Wewer MU, Zurakowski D, Pories ES, Moses MA. ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage. J Biol Chem 49:51323-51330, 2004.
O’Shea C, McKie N, Buggy Y, et al. Expression of ADAM-9 mRNA and protein in human breast cancer. Int J Cancer 105:754-761, 2003.
Lendeckel U, Kohl J, Arndt M, et al. Increased expression of ADAM family members in human breast cancer and breast cancer cell lines. J Cancer Res Clin Oncol 131:41-48, 2005.
Kuefer R, Day KC, Kleer CG, et al. ADAM15 disintegrin is associated with aggressive prostate and breast cancer diseases. Neoplasia 8:319–329, 2006.
Fröhlich C, Albrechtsen R, Dyrskjot L, et al. Molecular profiling of ADAM12 in human bladder cancer. Clin Cancer Res 12:7359-7368, 2006.
Kodama T, Ikeda E, Okada A, et al. ADAM12 is selectively overexpressed in human glioblastomas and is associated with glioblastoma cell proliferation and shedding of heparin-binding epidermal growth factor. Am J Pathol 165:1743–1753, 2004.
Read_full_article: pdf/20-2010/20-3-2010/SU20-3-10Narita.pdf
Correspondence: Dr. Diana Narita, MD, PhD, Department of Biochemistry, University of Medicine and Pharmacy “Victor Babes”, Eftimie Murgu Square No. 2A, 300041 Timisoara, Romania, Tel/Fax: 0040-56-220479, Email: diana_narita@yahoo.com

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Article Title: ADAM17 gene expression in laser-capture microdissected breast cancers
Authors: Diana Narita1*, Edward Seclaman1, Razvan Ilina1, Natalia Cireap1, George Ciprian Pribac2, Aurel Ardelean2, Tiberiu Nicola1, Andrei Anghel1
Affiliation: 1 University of Medicine and Pharmacy “Victor Babes”, Timisoara, Romania
2 “Vasile Goldis” Western University, Institute of Life Sciences, Arad, Romania
Abstract: Background. ADAMS (a desintegrin and metalloprotease) are transmembrane multifunctional glycoproteins, involved in cell growth, differentiation, motility, cell signaling and respectively, tumor growth, progression and spread. Our aim was to evaluate ADAM17 gene expression in homogenous, laser-capture microdissected breast cancers and to correlate their level of expression with cancers clinical and pathological characteristics. Materials and Methods. Expression of ADAM17 was analyzed using quantitative reverse-transcription polymerase chain reaction in laser-capture microdissected breast cancers specimens and corresponding non-neoplastic breast tissues from 38 patients. Results. We measured significantly elevated amounts of ADAM17 transcripts in malignant breast cells compared with normal adjacent breast tissue. Increased expression of ADAM17 showed high-grade cancers (p=0.04), but any significant differences were found related to age, stage, histology, tumor size, nodal, and ER/PR status; although not statistically significant, increased ADAM17 expressions showed HER2/neu positive, highly proliferative (high Ki67) and metastasized cancers. Conclusions. Our study provides further evidence of ADAM17 up-regulations in breast cancers and confers further motivation for future work on development of ADAM-selective inhibitors for cancers treatment.
Keywords: ADAM17, gene expression, laser-capture microdissection, breast cancers
References: Blobel CP. ADAMS: key components in EGFR signalling and development. Nat Rev Cancer, 6:32-43, 2005.
Arribas J, Bech-Serra JJ, Santiago-Josefat B ADAMs, cell migration and cancer. Cancer Metastasis Rev 25:57–68, 2006.
Ohtsu H, Dempsey PJ, Eguchi S ADAMs as mediators of EGF receptor transactivation by G-protein-coupled receptors. Am J Physiol Cell Physiol 291:C1–10, 2006
Mochizuki A, Okada Y ADAMs in cancer cell proliferation and progression. Cancer Sci 98:621-628, 2007.
Murphy G The ADAMs: signalling scissors in the tumor microenvironment. Nature Reviews Cancer, 8:929-941, 2008
Edwards DR, Handsley MM, Pennington CJ The ADAM metalloproteinases. Mol Aspects Med 29:258–289, 2008.
Duffy MJ, McKiernan E, O’Donovan N, McGowan P. Role of ADAMs in Cancer Formation and Progression. Clin Cancer Res 15:1140-1144, 2009.
McGowan PM, McKiernan E, Bolster F, et al. ADAM-17 predicts adverse outcome in patients with breast cancer. Ann Oncol 19:1075-1081, 2008.
Minn AJ, Kang Y, Serganova I,Gupta GP, Giri DD, Doubrovin M, Ponomarev V, Gerald WL, Blasberg R, Massagué J. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors.J Clin Invest, 115, 44-55, 2005.
Borrell-Pages M, Rojo F, Albanell J, Baselga J, Arribas J. TACE is required for the activation of the EGFR by TGF-alpha in tumors. EMBO J 22:1114–1124, 2003.
Zheng Y, Saftig P, Hartmann D, Blobel C. Evaluation of the contribution of different ADAMs to tumor necrosis factor α (TNF α) shedding and of the function of the TNF α ectodomain in ensuring selective stimulated shedding by the TNF α convertase (TACE/ADAM17). J Biol Chem 41:42898-42906, 2004.
Zucker S, Cao J, Chen WT. Critical appraisal of the use of matrix metalloproteinases inhibitors in cancer treatment. Oncogene 19:6642–6650, 2000.
Zhou BB, Petyon M, He B, et al. Targeting ADAM-mediated ligand cleavage toinhibit HER2 and EGFR pathways in non-small cell lung cancer. Cancer Cell 10:39–50, 2006.
Liu X, Fridman JS, Wang Q et al. Selective inhibition of ADAM metalloproteases blocks HER-2 extracellular domain (ECD) cleavage and potentiates the anti-tumor effects of trastuzumab. Cancer Biol Ther 5:648–656, 2006.
Fridman JS, Caulder E, Hansbury M. Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer. Clin Cancer Res 13:1892–1902, 2007.
De Kok JB, Roelofs RW, Giesendorf BA et al. Normalization of gene expression measurements in tumor tissues: comparison of 13 endogenous control genes. Lab Invest 85:154-159, 2005.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods 25:402-408, 2000.
Iba K, Albrechtsen R, Gilpin B, Fröhlich C, et al. The cysteine-rich domain of human ADAM 12 supports cell adhesion through syndecans and triggers signaling events that lead to β1 integrin-dependent cell spreading. J Cell Biol 149:1143–56, 2000.
Atfi A, Dumont E, Colland F, et al. The disintegrin and metalloproteinase ADAM12 contributes to TGF-β signaling through interaction with the type II receptor. J Cell Biol 178:201–208, 2007.
Dyczynska E, Syta E, Sun D, Zolkiewska A Breast cancer-associated mutations in metalloprotease disintegrin ADAM12 interfere with the intracellular trafficking and processing of the protein. Int J Cancer 122:2634-2640, 2008.
Le Pabic H, Bonnier D, Wewer UM, et al. ADAM12 in human liver cancers: TGF-β-regulated expression in stellate cells is associated with matrix remodeling. Hepatology 37:1056–1066, 2003.
Pories S, Zurakowski D, Roy R, et al. Urinary metalloproteinases: noninvasive biomarkers for breast cancer risk assessment. Cancer Epidemiol Biomarkers Prev, 17:1034-1042, 2008.
Shi Z, Xu W, Loechel F, Wewer UM, Murphy LJ. ADAM12, a disintegrin and metalloprotease, interacts with insulin-like growth factor-binding protein-3. J Biol Chem 275:18 574–18 580, 2000.
Laigaard J, Sørensen T, Fröhlich C, et al. ADAM12: a novel first-trimester maternal serum marker for Down syndrome. Prenat Diagn 23:1086–1091, 2003.
Roy R, Wewer MU, Zurakowski D, Pories ES, Moses MA. ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage. J Biol Chem 49:51323-51330, 2004.
O’Shea C, McKie N, Buggy Y, et al. Expression of ADAM-9 mRNA and protein in human breast cancer. Int J Cancer 105:754-761, 2003.
Lendeckel U, Kohl J, Arndt M, et al. Increased expression of ADAM family members in human breast cancer and breast cancer cell lines. J Cancer Res Clin Oncol 131:41-48, 2005.
Kuefer R, Day KC, Kleer CG, et al. ADAM15 disintegrin is associated with aggressive prostate and breast cancer diseases. Neoplasia 8:319–329, 2006.
Fröhlich C, Albrechtsen R, Dyrskjot L, et al. Molecular profiling of ADAM12 in human bladder cancer. Clin Cancer Res 12:7359-7368, 2006.
Kodama T, Ikeda E, Okada A, et al. ADAM12 is selectively overexpressed in human glioblastomas and is associated with glioblastoma cell proliferation and shedding of heparin-binding epidermal growth factor. Am J Pathol 165:1743–1753, 2004.
*Correspondence: Dr. Diana Narita, MD, PhD, Department of Biochemistry, University of Medicine and Pharmacy “Victor Babes”, Eftimie Murgu Square No. 2A, 300041 Timisoara, Romania, Tel/Fax: 0040-56-220479, Email: diana_narita@yahoo.com