Extensive expression of craniofacial related homeobox genes in canine mammary sarcomas

Abstract

Extensive expression of craniofacial related homeobox genes in canine mammary sarcomas Journal Breast Cancer Research and Treatment Publisher Springer Netherlands ISSN 0167-6806 (Print) 1573-7217 (Online) Issue Volume 118, Number 2 / November, 2009 Category Preclinical Study DOI 10.1007/s10549-008-0243-7 Pages 333-343 Subject Collection Medicine SpringerLink Date Tuesday, December 02, 2008 Preclinical Study Extensive expression of craniofacial related homeobox genes in canine mammary sarcomas Helena Wensman1 , Hanna Göransson2, Karl-Johan Leuchowius3, Sara Strömberg3, Fredrik Pontén3, Anders Isaksson2, Gerard Roel Rutteman4, Nils-Erik Heldin3, Gunnar Pejler1 and Eva Hellmén1 (1) Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, P.O.Box 7011, 750 07 Uppsala, Sweden (2) Department of Medical Sciences, Uppsala University, Uppsala, Sweden (3) Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden (4) Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands Received: 10 September 2008 Accepted: 30 October 2008 Published online: 2 December 2008 Abstract The global gene expression in three types of canine mammary tumors: carcinoma, fibrosarcoma and osteosarcoma were investigated by Affymetrix gene array technology. Unsupervised clustering analysis revealed a close clustering of the respective tumor types, with fibrosarcomas clustering close to the osteosarcomas and the carcinomas clustering closer to non-malignant mammary tissues (NMTs). A number of epithelial markers were expressed in both carcinomas and NMTs, whereas the sarcomas expressed genes related to mesenchymal differentiation. A comparison of the gene expression profile of the sarcomas versus carcinoma/NMTs revealed that the sarcomas, in particular the osteosarcomas, showed a striking upregulation of a panel of homeobox genes previously linked to craniofacial bone formation. In line with this finding, osteosarcomas showed an upregulation of bone morphogenetic proteins (BMPs) and of genes associated with retinoic acid signaling. Increased homeobox gene expression in sarcomas was also confirmed at the protein level by immunohistochemical analysis of tumor tissue, and in an osteosarcoma cell line after stimulation by BMP-2. These findings suggest that the development of mammary sarcomas specifically involves triggering of a set of homeobox genes related to neural crest and craniofacial bone development. Electronic supplementary material The online version of this article (doi:10.1007/s10549-008-0243-7) contains supplementary material, which is available to authorized users. Keywords Canine mammary tumors - Mammary sarcoma - Mammary osteosarcoma - Homeobox transcription factor - Gene expression profiling - Craniofacial