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A novel myoepithelial cell marker in canine mammary tissue
The Veterinary Journal 190 (2011) 303–304
Contents lists available at ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Guest Editorial
A novel myoepithelial cell marker in canine mammary tissue Mammary tumours are the most common canine neoplasm, with malignant variants accounting for up to 50% of cases (Sorenmo, 2003). These tumours are quite heterogeneous in terms of morphology and biological behaviour (Nerurkar et al., 1989; Misdorp, 2002), and have been the focus of intensive research over the last few decades. Although immunohistochemistry, coupled with standard histopathological assessment, plays a significant role in the diagnosis and prognosis of breast cancer in human patients (Payne et al., 2008), its use in context of veterinary medicine is under-developed. As a result, work aimed at identifying novel diagnostic and/or prognostically useful immunohistochemical markers in canine mammary tumours is timely. The paper by Alejandro Suárez-Bonnet of the Institute for Animal Health at the University of Las Palmas de Gran Canaria, published in this issue of The Veterinary Journal, evaluates the 14-3-3r protein as a novel myoepithelial cell marker in canine mammary tissue (Suárez-Bonnet et al., 2011). Given the difficulties in identifying myoepithelial cells in routinely stained tissue sections, several immunohistochemical markers have been used to demonstrate their presence and thus assist in the diagnosis of neoplasms with a myoepithelial component (Gama et al., 2003; Goldschmidt et al., 2011; Sorenmo et al., 2011). Such markers are particularly helpful in detecting stromal invasion, a feature that facilitates the differentiation of in situ from invasive carcinomas (Yaziji et al., 2000; Espinosa de los Monteros et al., 2002). Cell markers such as basal cytokeratins (CK5, CK14 and CK17) (Griffey et al., 1993; Vos et al., 1993a–c), p63 (Gama et al., 2003; Ramalho et al., 2006), a-smooth muscle actin (Destexhe et al., 1993a; Vos et al., 1993a–c) and calponin (Espinosa de los Monteros et al., 2002), have all previously been proposed as myoepithelial cell markers in canine mammary tissue. Should the 14-3-3r protein joint this list? Suárez-Bonnet et al. (2011) examined the expression of the 14-33r protein in canine mammary tissue using both immunohistochemistry and Western blot analysis. Western blotting revealed that an anti-human 14-3-3r monoclonal antibody specifically recognised the canine protein, which was preferentially expressed by mammary myoepithelial cells in normal, dysplastic and neoplastic samples. Using a double-immunohistochemical technique to label both 14-3-3r and p63, the authors demonstrated that 14-3-3r is a highly sensitive, albeit non-specific, myoepithelial marker. The 14-3-3r protein was also found in neoplastic epithelial cells in a considerable number of the benign and malignant neoplasms examined, and several carcinomas were characterised by co-expression of 14-3-3r and p63, suggesting these tumours might be exhibiting basal/myoepithelial differentiation. A number of immunohistochemical studies of both human and canine mammary tumours have indicated the presence of a basal/ myoepithelial cell phenotype in a subset of carcinomas which were 1090-0233/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2011.04.016
not readily recognisable on routine histopathological evaluation (Destexhe et al., 1993b; Griffey et al., 1993; Gama et al., 2003, 2008), and were characterised by aggressive behaviour and carried a poor prognosis (Griffey et al., 1993; Tsuda et al., 2000; Jones et al., 2001; Laakso et al., 2005; Gama et al., 2008). In the study outlined by Suárez-Bonnet et al. (2011) intense 14-3-3r expression was detected in the majority of aggressive tumours, such as those exhibiting vascular invasion and metastasis to lymph nodes. This suggests 14-3-3r may have a role in enhancing the invasive capacity of such neoplasms, possibly through the activation of matrix metalloproteinase expression by fibroblasts in the tumour microenvironment, as has been demonstrated in a keratinocyte/fibroblast co-culture system (Ghahary et al., 2004, 2005). It would appear that 14-3-3r is more than just a myoepithelial cell marker. Li et al. (2009) found that 14-3-3r may act as a ‘double-edged sword’ in the context of human cancers, in that it appears in some to function as a tumour suppressor with decreased expression contributing to tumourigenesis, whilst in others it may be involved in tissue invasion and metastasis. This apparently ambivalent functionality is probably associated with the role of 143-3r as chaperone to a diverse range of protein ligands implicated in a range of cellular processes including cell-cycle checkpoint regulation and apoptosis in response to DNA injury (Li et al., 2009). Suárez-Bonnet et al. (2011) have launched 14-3-3r in the context of veterinary research, where future work will hopefully unravel its role in canine mammary tumourigenesis and further assess its potential as a diagnostic/prognostic biomarker. Adelina Gama Department of Veterinary Sciences, Animal and Veterinary Science Research Center (CECAV), University of Trás-os-Montes and Alto Douro (UTAD), 5001-801 Vila Real, Portugal E-mail address: [email protected]
References Destexhe, E., Bicker, E., Coignoul, F., 1993a. Image analysis evaluation of ploidy, S-phase fraction and nuclear area in canine mammary tumours. Journal of Comparative Pathology 113, 205–216. Destexhe, E., Lespagnard, L., Degeyter, M., Heymann, R., Coignoul, F., 1993b. Immunohistochemical identification of myoepithelial, epithelial, and connective tissue cells in canine mammary tumors. Veterinary Pathology 30, 146–154. Espinosa de Los Monteros, A., Millán, M.Y., Ordás, J., Carrasco, L., Reymundo, C., Martín de Las Mulas, J., 2002. Immunolocalization of the smooth musclespecific protein calponin in complex and mixed tumors of the mammary gland of the dog: Assessment of the morphogenetic role of the myoepithelium. Veterinary Pathology 39, 247–256.
304
Guest Editorial / The Veterinary Journal 190 (2011) 303–304
Gama, A., Alves, A., Gärtner, F., Schmitt, F., 2003. P63: A novel myoepithelial cell marker in canine mammary tissues. Veterinary Pathology 40, 412–420. Gama, A., Alves, A., Schmitt, F., 2008. Identification of molecular phenotypes in canine mammary carcinomas with clinical implications: Application of the human classification. Virchows Archiv 453, 123–132. Ghahary, A., Karimi-Busheri, F., Marcoux, Y., Li, Y., Tredget, E.E., Taghi Kilani, R., Li, L., Zheng, J., Karami, A., Keller, B.O., Weinfeld, M., 2004. Keratinocyte-releasable stratifin functions as a potent collagenase-stimulating factor in fibroblasts. Journal of Investigative Dermatology 122, 1188–1197. Ghahary, A., Marcoux, Y., Karimi-Busheri, F., Li, Y., Tredget, E.E., Kilani, R.T., Lam, E., Weinfeld, M., 2005. Differentiated keratinocyte-releasable stratifin (14-3-3r) stimulates MMP-1 expression in dermal fibroblasts. Journal of Investigative Dermatology 124, 170–177. Goldschmidt, M., Peña, L., Rasotto, R., Zappulli, V., 2011. Classification and grading of canine mammary tumors. Veterinary Pathology 48, 117–131. Griffey, S.M., Madewell, B.R., Dairkee, S.H., Hunt, J.E., Naydan, D.K., Higgins, R.J., 1993. Immunohistochemical reactivity of basal and luminal epithelium-specific cytokeratin antibodies within normal and neoplastic canine mammary glands. Veterinary Pathology 30, 155–161. Jones, C., Nonni, A.V., Fulford, L., Merrett, S., Chaqqar, R., Eusebi, V., Lakhani, S.R., 2001. CGH analysis of ductal carcinoma of the breast with basaloid/ myoepithelial cell differentiation. British Journal of Cancer 85, 422–427. Laakso, M., Loman, N., Borg, A., Isola, J., 2005. Cytokeratin 5/14-positive breast cancer: True basal phenotype confined to BRCA1 tumors. Modern Pathology 18, 1321–1328. Li, Z., Liu, J.Y., Zhang, J.T., 2009. 14-3-3r, the double-edged sword of human cancers. American Journal of Translational Research 1, 326–340. Misdorp, W., 2002. Tumours of the mammary gland. In: Meuten, D.J. (Ed.), Tumors in Domestic Animals, fourth Ed. Iowa State Press, Blackwell Publishing Company, USA, pp. 575–606. Nerurkar, V.R., Chitale, A.R., Jalnakurpar, B.V., Naik, S.N., Lalitha, V.S., 1989. Comparative pathology of canine mammary tumours. Journal of Comparative Pathology 101, 389–397. Payne, S.J.L., Bowen, R.L., Jones, J.L., Wells, C.A., 2008. Predictive markers in breast cancer – The present. Histopathology 52, 82–90.
Ramalho, L.N., Ribeiro-Silva, A., Cassali, G.D., Zucoloto, S., 2006. The expression of p63 and cytokeratin 5 in mixed tumors of the canine mammary gland provides new insights into the histogenesis of these neoplasms. Veterinary Pathology 43, 424–429. Sorenmo, K., 2003. Canine mammary gland tumors. Veterinary Clinics of North America: Small Animal Practice 33, 573–596. Sorenmo, K.U., Rasotto, R., Zappulli, V., Goldschmidt, M.H., 2011. Development, anatomy, histology, lymphatic drainage, clinical features, and cell differentiation markers of canine mammary gland neoplasms. Veterinary Pathology 48, 85–97. Suárez-Bonnet, A., Herráez, P., Mulas, J.M., Rodríguez, F., Déniz, J.M., Monteros, A.E., 2011. Expression of 14-3-3r protein in normal and neoplastic canine mammary gland. The Veterinary Journal 190, 345–351. Tsuda, H., Takarabe, T., Hasegawa, F., Fukutomi, T., Hirohashi, S., 2000. Large, central acellular zones indicating myoepithelial tumor differentiation in high-grade invasive ductal carcinomas as markers of predisposition to lung and brain metastases. The American Journal of Surgical Pathology 24, 197–202. Vos, J.H., Van den Ingh, T.S., Misdorp, W., Molenbeek, R.F., Van Mil, F.N., Rutterman, G.R., Ivanyi, D., Ramaekers, F.C.S., 1993a. Immunohistochemistry with keratin, vimentin, desmin, and (-smooth muscle actin monoclonal antibodies in canine mammary gland: Benign mammary tumors and duct ectasias. Veterinary Quarterly 14, 89–95. Vos, J.H., Van den Ingh, T.S., Misdorp, W., Molenbeek, R.F., Van Mil, F.N., Rutterman, G.R., Ivanyi, D., Ramaekers, F.C.S., 1993b. Immunohistochemistry with keratin, vimentin, desmin, and (-smooth muscle actin monoclonal antibodies in canine mammary gland: Malignant mammary tumors. Veterinary Quarterly 14, 96– 102. Vos, J.H., Van den Ingh, T.S., Misdorp, W., Molenbeek, R.F., Van Mil, F.N., Rutterman, G.R., Ivanyi, D., Ramaekers, F.C.S., 1993c. Immunohistochemistry with keratin, vimentin, desmin, and (-smooth muscle actin monoclonal antibodies in canine mammary gland: Normal mammary tissue. Veterinary Quarterly 14, 102–107. Yaziji, H., Gown, A.M., Sneige, N., 2000. Detection of stromal invasion in breast cancer: The myoepithelial markers. Advances in Anatomic Pathology 7, 100– 109.
Contents lists available at ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Guest Editorial
A novel myoepithelial cell marker in canine mammary tissue Mammary tumours are the most common canine neoplasm, with malignant variants accounting for up to 50% of cases (Sorenmo, 2003). These tumours are quite heterogeneous in terms of morphology and biological behaviour (Nerurkar et al., 1989; Misdorp, 2002), and have been the focus of intensive research over the last few decades. Although immunohistochemistry, coupled with standard histopathological assessment, plays a significant role in the diagnosis and prognosis of breast cancer in human patients (Payne et al., 2008), its use in context of veterinary medicine is under-developed. As a result, work aimed at identifying novel diagnostic and/or prognostically useful immunohistochemical markers in canine mammary tumours is timely. The paper by Alejandro Suárez-Bonnet of the Institute for Animal Health at the University of Las Palmas de Gran Canaria, published in this issue of The Veterinary Journal, evaluates the 14-3-3r protein as a novel myoepithelial cell marker in canine mammary tissue (Suárez-Bonnet et al., 2011). Given the difficulties in identifying myoepithelial cells in routinely stained tissue sections, several immunohistochemical markers have been used to demonstrate their presence and thus assist in the diagnosis of neoplasms with a myoepithelial component (Gama et al., 2003; Goldschmidt et al., 2011; Sorenmo et al., 2011). Such markers are particularly helpful in detecting stromal invasion, a feature that facilitates the differentiation of in situ from invasive carcinomas (Yaziji et al., 2000; Espinosa de los Monteros et al., 2002). Cell markers such as basal cytokeratins (CK5, CK14 and CK17) (Griffey et al., 1993; Vos et al., 1993a–c), p63 (Gama et al., 2003; Ramalho et al., 2006), a-smooth muscle actin (Destexhe et al., 1993a; Vos et al., 1993a–c) and calponin (Espinosa de los Monteros et al., 2002), have all previously been proposed as myoepithelial cell markers in canine mammary tissue. Should the 14-3-3r protein joint this list? Suárez-Bonnet et al. (2011) examined the expression of the 14-33r protein in canine mammary tissue using both immunohistochemistry and Western blot analysis. Western blotting revealed that an anti-human 14-3-3r monoclonal antibody specifically recognised the canine protein, which was preferentially expressed by mammary myoepithelial cells in normal, dysplastic and neoplastic samples. Using a double-immunohistochemical technique to label both 14-3-3r and p63, the authors demonstrated that 14-3-3r is a highly sensitive, albeit non-specific, myoepithelial marker. The 14-3-3r protein was also found in neoplastic epithelial cells in a considerable number of the benign and malignant neoplasms examined, and several carcinomas were characterised by co-expression of 14-3-3r and p63, suggesting these tumours might be exhibiting basal/myoepithelial differentiation. A number of immunohistochemical studies of both human and canine mammary tumours have indicated the presence of a basal/ myoepithelial cell phenotype in a subset of carcinomas which were 1090-0233/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2011.04.016
not readily recognisable on routine histopathological evaluation (Destexhe et al., 1993b; Griffey et al., 1993; Gama et al., 2003, 2008), and were characterised by aggressive behaviour and carried a poor prognosis (Griffey et al., 1993; Tsuda et al., 2000; Jones et al., 2001; Laakso et al., 2005; Gama et al., 2008). In the study outlined by Suárez-Bonnet et al. (2011) intense 14-3-3r expression was detected in the majority of aggressive tumours, such as those exhibiting vascular invasion and metastasis to lymph nodes. This suggests 14-3-3r may have a role in enhancing the invasive capacity of such neoplasms, possibly through the activation of matrix metalloproteinase expression by fibroblasts in the tumour microenvironment, as has been demonstrated in a keratinocyte/fibroblast co-culture system (Ghahary et al., 2004, 2005). It would appear that 14-3-3r is more than just a myoepithelial cell marker. Li et al. (2009) found that 14-3-3r may act as a ‘double-edged sword’ in the context of human cancers, in that it appears in some to function as a tumour suppressor with decreased expression contributing to tumourigenesis, whilst in others it may be involved in tissue invasion and metastasis. This apparently ambivalent functionality is probably associated with the role of 143-3r as chaperone to a diverse range of protein ligands implicated in a range of cellular processes including cell-cycle checkpoint regulation and apoptosis in response to DNA injury (Li et al., 2009). Suárez-Bonnet et al. (2011) have launched 14-3-3r in the context of veterinary research, where future work will hopefully unravel its role in canine mammary tumourigenesis and further assess its potential as a diagnostic/prognostic biomarker. Adelina Gama Department of Veterinary Sciences, Animal and Veterinary Science Research Center (CECAV), University of Trás-os-Montes and Alto Douro (UTAD), 5001-801 Vila Real, Portugal E-mail address: [email protected]
References Destexhe, E., Bicker, E., Coignoul, F., 1993a. Image analysis evaluation of ploidy, S-phase fraction and nuclear area in canine mammary tumours. Journal of Comparative Pathology 113, 205–216. Destexhe, E., Lespagnard, L., Degeyter, M., Heymann, R., Coignoul, F., 1993b. Immunohistochemical identification of myoepithelial, epithelial, and connective tissue cells in canine mammary tumors. Veterinary Pathology 30, 146–154. Espinosa de Los Monteros, A., Millán, M.Y., Ordás, J., Carrasco, L., Reymundo, C., Martín de Las Mulas, J., 2002. Immunolocalization of the smooth musclespecific protein calponin in complex and mixed tumors of the mammary gland of the dog: Assessment of the morphogenetic role of the myoepithelium. Veterinary Pathology 39, 247–256.
304
Guest Editorial / The Veterinary Journal 190 (2011) 303–304
Gama, A., Alves, A., Gärtner, F., Schmitt, F., 2003. P63: A novel myoepithelial cell marker in canine mammary tissues. Veterinary Pathology 40, 412–420. Gama, A., Alves, A., Schmitt, F., 2008. Identification of molecular phenotypes in canine mammary carcinomas with clinical implications: Application of the human classification. Virchows Archiv 453, 123–132. Ghahary, A., Karimi-Busheri, F., Marcoux, Y., Li, Y., Tredget, E.E., Taghi Kilani, R., Li, L., Zheng, J., Karami, A., Keller, B.O., Weinfeld, M., 2004. Keratinocyte-releasable stratifin functions as a potent collagenase-stimulating factor in fibroblasts. Journal of Investigative Dermatology 122, 1188–1197. Ghahary, A., Marcoux, Y., Karimi-Busheri, F., Li, Y., Tredget, E.E., Kilani, R.T., Lam, E., Weinfeld, M., 2005. Differentiated keratinocyte-releasable stratifin (14-3-3r) stimulates MMP-1 expression in dermal fibroblasts. Journal of Investigative Dermatology 124, 170–177. Goldschmidt, M., Peña, L., Rasotto, R., Zappulli, V., 2011. Classification and grading of canine mammary tumors. Veterinary Pathology 48, 117–131. Griffey, S.M., Madewell, B.R., Dairkee, S.H., Hunt, J.E., Naydan, D.K., Higgins, R.J., 1993. Immunohistochemical reactivity of basal and luminal epithelium-specific cytokeratin antibodies within normal and neoplastic canine mammary glands. Veterinary Pathology 30, 155–161. Jones, C., Nonni, A.V., Fulford, L., Merrett, S., Chaqqar, R., Eusebi, V., Lakhani, S.R., 2001. CGH analysis of ductal carcinoma of the breast with basaloid/ myoepithelial cell differentiation. British Journal of Cancer 85, 422–427. Laakso, M., Loman, N., Borg, A., Isola, J., 2005. Cytokeratin 5/14-positive breast cancer: True basal phenotype confined to BRCA1 tumors. Modern Pathology 18, 1321–1328. Li, Z., Liu, J.Y., Zhang, J.T., 2009. 14-3-3r, the double-edged sword of human cancers. American Journal of Translational Research 1, 326–340. Misdorp, W., 2002. Tumours of the mammary gland. In: Meuten, D.J. (Ed.), Tumors in Domestic Animals, fourth Ed. Iowa State Press, Blackwell Publishing Company, USA, pp. 575–606. Nerurkar, V.R., Chitale, A.R., Jalnakurpar, B.V., Naik, S.N., Lalitha, V.S., 1989. Comparative pathology of canine mammary tumours. Journal of Comparative Pathology 101, 389–397. Payne, S.J.L., Bowen, R.L., Jones, J.L., Wells, C.A., 2008. Predictive markers in breast cancer – The present. Histopathology 52, 82–90.
Ramalho, L.N., Ribeiro-Silva, A., Cassali, G.D., Zucoloto, S., 2006. The expression of p63 and cytokeratin 5 in mixed tumors of the canine mammary gland provides new insights into the histogenesis of these neoplasms. Veterinary Pathology 43, 424–429. Sorenmo, K., 2003. Canine mammary gland tumors. Veterinary Clinics of North America: Small Animal Practice 33, 573–596. Sorenmo, K.U., Rasotto, R., Zappulli, V., Goldschmidt, M.H., 2011. Development, anatomy, histology, lymphatic drainage, clinical features, and cell differentiation markers of canine mammary gland neoplasms. Veterinary Pathology 48, 85–97. Suárez-Bonnet, A., Herráez, P., Mulas, J.M., Rodríguez, F., Déniz, J.M., Monteros, A.E., 2011. Expression of 14-3-3r protein in normal and neoplastic canine mammary gland. The Veterinary Journal 190, 345–351. Tsuda, H., Takarabe, T., Hasegawa, F., Fukutomi, T., Hirohashi, S., 2000. Large, central acellular zones indicating myoepithelial tumor differentiation in high-grade invasive ductal carcinomas as markers of predisposition to lung and brain metastases. The American Journal of Surgical Pathology 24, 197–202. Vos, J.H., Van den Ingh, T.S., Misdorp, W., Molenbeek, R.F., Van Mil, F.N., Rutterman, G.R., Ivanyi, D., Ramaekers, F.C.S., 1993a. Immunohistochemistry with keratin, vimentin, desmin, and (-smooth muscle actin monoclonal antibodies in canine mammary gland: Benign mammary tumors and duct ectasias. Veterinary Quarterly 14, 89–95. Vos, J.H., Van den Ingh, T.S., Misdorp, W., Molenbeek, R.F., Van Mil, F.N., Rutterman, G.R., Ivanyi, D., Ramaekers, F.C.S., 1993b. Immunohistochemistry with keratin, vimentin, desmin, and (-smooth muscle actin monoclonal antibodies in canine mammary gland: Malignant mammary tumors. Veterinary Quarterly 14, 96– 102. Vos, J.H., Van den Ingh, T.S., Misdorp, W., Molenbeek, R.F., Van Mil, F.N., Rutterman, G.R., Ivanyi, D., Ramaekers, F.C.S., 1993c. Immunohistochemistry with keratin, vimentin, desmin, and (-smooth muscle actin monoclonal antibodies in canine mammary gland: Normal mammary tissue. Veterinary Quarterly 14, 102–107. Yaziji, H., Gown, A.M., Sneige, N., 2000. Detection of stromal invasion in breast cancer: The myoepithelial markers. Advances in Anatomic Pathology 7, 100– 109.