Extensive expression of craniofacial related homeobox genes in canine mammary sarcomas

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 - Craniofacia

Novel and highly recurrent chromosomal alterations in Sezary syndrome.

Contains fulltext : 71220.pdf (publisher's version ) (Closed access)This study was designed to identify highly recurrent genetic alterations typical of Sezary syndrome (Sz), an aggressive cutaneous T-cell lymphoma/leukemia, possibly revealing pathogenetic mechanisms and novel therapeutic targets. High-resolution array-based comparative genomic hybridization was done on malignant T cells from 20 patients. Expression levels of selected biologically relevant genes residing within loci with frequent copy number alteration were measured using quantitative PCR. Combined binary ratio labeling-fluorescence in situ hybridization karyotyping was done on malignant cells from five patients. Minimal common regions with copy number alteration occurring in at least 35% of patients harbored 15 bona fide oncogenes and 3 tumor suppressor genes. Based on the function of the identified oncogenes and tumor suppressor genes, at least three molecular mechanisms are relevant in the pathogenesis of Sz. First, gain of cMYC and loss of cMYC antagonists (MXI1 and MNT) were observed in 75% and 40% to 55% of patients, respectively, which were frequently associated with deregulated gene expression. The presence of cMYC/MAX protein heterodimers in Sezary cells was confirmed using a proximity ligation assay. Second, a region containing TP53 and genome maintenance genes (RPA1/HIC1) was lost in the majority of patients. Third, the interleukin 2 (IL-2) pathway was affected by gain of STAT3/STAT5 and IL-2 (receptor) genes in 75% and 30%, respectively, and loss of TCF8 and DUSP5 in at least 45% of patients. In sum, the Sz genome is characterized by gross chromosomal instability with highly recurrent gains and losses. Prominent among deregulated genes are those encoding cMYC, cMYC-regulating proteins, mediators of MYC-induced apoptosis, and IL-2 signaling pathway components