The metastatic cascade is reflected in the transcriptome of metastatic canine mammary carcinomas.
Proliferation, dedifferentiation and loss of cell-cell contacts are amongst the first steps of the metastatic cascade. The complex molecular pathways and gene expression changes associated with these events in canine mammary tumors are still largely undetermined. In this study, the transcriptome of 13 lymph node positive canine mammary carcinomas and corresponding non-neoplastic mammary glands were compared to identify the molecular pathways associated with metastatic progression. Differential gene expression was analyzed using gene set enrichment and pathway analysis and compared with gene expression data from human breast cancer. Metastatic canine carcinomas had 1312 significantly differentially expressed genes compared to normal mammary glands. This expression profile included a significant up-regulation of cell division and matrix invasion genes (MMP, SERPINE1, TIMP3). In contrast, genes associated with epithelial differentiation (EGF, EGFR, MAP2K6, STAT 5), cell adhesion (CLDN5, CTNNAL1, MUC1, PECAM1) and angiogenesis (ANGPT 2, ANGPTL1-4, FIGF, TIE1) were mostly down-regulated. Tumors had a significant decrease in membrane receptors and pathway gene expression (EGFR, FGFR1, GHR, PDGFR, TGFBR, TIE1) indicating a tendency towards independence from these proliferative stimuli. A number of the identified deregulated pathways overlapped with gene expression profiles of human breast cancer. Gene expression profiling of metastatic carcinomas, therefore, identified molecular pathways and functional gene families that are deregulated during malignant progression in canine mammary tumors.
Department of Veterinary Pathology, Freie Universität Berlin, Robert-von-Ostertag-Straße 15, 14163 Berlin, Germany. Electronic address: klopfleisch.robert@vetmed.fu-berlin.de.
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Klopfleisch
Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Institute of Pathology, Hindenburgdamm 30, D-12200 Berlin, Germany.
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Lenze
Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Institute of Pathology, Hindenburgdamm 30, D-12200 Berlin, Germany.
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Hummel
Department of Veterinary Pathology, Freie Universität Berlin, Robert-von-Ostertag-Straße 15, 14163 Berlin, Germany.
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Gruber
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D004283:Dog Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D005260:Female; D020869:Gene Expression Profiling / Q000662:veterinary; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics*; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000662:veterinary; D012333:RNA, Messenger / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D059467:Transcriptome
D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen