Project description:[original title] Metastatic Canine Mammary Carcinomas can be Identified by a Gene Expression Profile that partly Overlaps with Human Breast Cancer Profiles. Introduction: Similar to human breast cancer mammary tumors of the female dog are commonly associated with a fatal outcome due to the development of distant metastases. However, the molecular defects leading to metastasis are largely unknown and the value of canine mammary carcinoma as a model for human breast cancer is unclear. In this study, we analyzed the gene expression signatures associated with mammary tumor metastasis and asked for parallels with the human equivalent. Methods: Messenger RNA expression profiles of twenty-seven lymph node metastasis positive or negative canine mammary carcinomas were established by microarray analysis. Differentially expressed genes were functionally characterized and associated with molecular pathways. The findings were also correlated with published data on human breast cancer. Results: Metastatic canine mammary carcinomas had 1,011 significantly differentially expressed genes when compared to non-metastatic carcinomas. Metastatic carcinomas had a significant up-regulation of genes associated with cell cycle regulation, matrix modulation, protein folding and proteasomal degradation whereas cell differentiation genes, growth factor pathway genes and regulators of actin organization were significantly down-regulated. Interestingly, 265 of the 1,011 differentially expressed canine genes are also related to human breast cancer and, vice versa, parts of a human prognostic gene signature were identified in the expression profiles of the metastatic canine tumors. Conclusions: Metastatic canine mammary carcinomas can be discriminated from non-metastatic carcinomas by their gene expression profiles. More than one third of the differentially expressed genes are also described of relevance for human breast cancer. Many of the differentially expressed genes are linked to functions and pathways which appear to be relevant for the induction and maintenance of metastatic progression and may represent new therapeutic targets. Furthermore, dogs are in some aspects suitable as a translational model for human breast tumors in order to identify prognostic molecular signatures and potential therapeutic targets.

Project description:[original title] Metastatic Canine Mammary Carcinomas can be Identified by a Gene Expression Profile that partly Overlaps with Human Breast Cancer Profiles. Introduction: Similar to human breast cancer mammary tumors of the female dog are commonly associated with a fatal outcome due to the development of distant metastases. However, the molecular defects leading to metastasis are largely unknown and the value of canine mammary carcinoma as a model for human breast cancer is unclear. In this study, we analyzed the gene expression signatures associated with mammary tumor metastasis and asked for parallels with the human equivalent. Methods: Messenger RNA expression profiles of twenty-seven lymph node metastasis positive or negative canine mammary carcinomas were established by microarray analysis. Differentially expressed genes were functionally characterized and associated with molecular pathways. The findings were also correlated with published data on human breast cancer. Results: Metastatic canine mammary carcinomas had 1,011 significantly differentially expressed genes when compared to non-metastatic carcinomas. Metastatic carcinomas had a significant up-regulation of genes associated with cell cycle regulation, matrix modulation, protein folding and proteasomal degradation whereas cell differentiation genes, growth factor pathway genes and regulators of actin organization were significantly down-regulated. Interestingly, 265 of the 1,011 differentially expressed canine genes are also related to human breast cancer and, vice versa, parts of a human prognostic gene signature were identified in the expression profiles of the metastatic canine tumors. Conclusions: Metastatic canine mammary carcinomas can be discriminated from non-metastatic carcinomas by their gene expression profiles. More than one third of the differentially expressed genes are also described of relevance for human breast cancer. Many of the differentially expressed genes are linked to functions and pathways which appear to be relevant for the induction and maintenance of metastatic progression and may represent new therapeutic targets. Furthermore, dogs are in some aspects suitable as a translational model for human breast tumors in order to identify prognostic molecular signatures and potential therapeutic targets. Thirteen simple mammary carcinomas with invasive growth and lymph node metastases at the time of tumor resection and 14 simple carcinomas without lymph node metastases were included in the study. None of the patients had radiographically detectable pulmonary metastases at the time of tumor resection. Distant metastases as the cause of death were determined postoperatively by radiographic detection of metastases or necropsy. Selection criteria for carcinomas without lymph node metastases included an invasive growth, a negative lymph node status, a histological grade III and a minimal tumor diameter above the average of the lymph node positive tumors (> 2.42 cm). All animals with non-metastatic carcinomas had a survival rate of over 24 months except animal no. 22 (2627) which developed radiographic detectable lung metastases 8 months after surgery. Tumor and lymph node histologies were evaluated independently by two board-certified pathologists, following the criteria of the WHO classification of canine mammary tumors and the Nottingham grading system. All 27 tumors were simple carcinomas and characterized by an invasive, mostly solid growth pattern, marked cellular pleomorphism, anisokaryosis and 3 or more mitotic figures per high power field.

Project description:Proliferation, dedifferentiation, loss of cell-cell contacts and angiogenesis are among the first steps of the metastasis cascade. The complex molecular pathways associated with these events in canine mammary tumors are mostly unknown and the value of this spontaneous canine tumor as a comparative model for human breast cancer is therefore still under debate. Messenger RNA profiles of lymph-node positive canine mammary carcinomas and normal mammary glands of the same dogs were compared by microarray analysis to elucidate molecular pathways associated with metastatic progression. Differential gene expression was analyzed by gene set enrichment and pathway analysis and compared with the gene expression data of human breast cancer. Metastatic canine carcinomas had 1,312 significantly differentially expressed genes when compared to the corresponding normal mammary gland. This expression profile included a significantly increased expression of cell division and extracellular matrix invasion genes (MMP1, MMP11, MMP13, SERPINE1, TFPI2, TIMP3). In contrast, genes associated with epithelial differentiation (EGF, EGFR, KRT17, MAP2K6, STAT5), cell adhesion (CLDN5, CLDN8, CTNNAL1, MCAM, MUC1, PECAM1) and angiogenesis (ANGPT2, ANGPTL1, ANGPTL2, ANGPTL4, FGFR1, FIGF, TIE1) were mostly down-regulated. Interestingly, tumors had a significant decrease in membrane receptors and growth factor pathway gene expression (EGFR, FGFR1, GHR, LYVE1, PDGFR, PDGFR, TGFBR, TIE1), indicating a potential independence from these proliferative stimuli. Several of the identified deregulated pathways overlap with gene expression profiles of human breast cancer. Gene expression profiling of metastatic carcinomas therefore identified complex molecular pathways and functional gene families that are deregulated during malignant progression in the tumors. This study provides new insights into canine mammary tumor metastasis and suggests that canine mammary tumors may serve as a valuable model for the human disease.

Project description:Proliferation, dedifferentiation, loss of cell-cell contacts and angiogenesis are among the first steps of the metastasis cascade. The complex molecular pathways associated with these events in canine mammary tumors are mostly unknown and the value of this spontaneous canine tumor as a comparative model for human breast cancer is therefore still under debate. Messenger RNA profiles of lymph-node positive canine mammary carcinomas and normal mammary glands of the same dogs were compared by microarray analysis to elucidate molecular pathways associated with metastatic progression. Differential gene expression was analyzed by gene set enrichment and pathway analysis and compared with the gene expression data of human breast cancer. Metastatic canine carcinomas had 1,312 significantly differentially expressed genes when compared to the corresponding normal mammary gland. This expression profile included a significantly increased expression of cell division and extracellular matrix invasion genes (MMP1, MMP11, MMP13, SERPINE1, TFPI2, TIMP3). In contrast, genes associated with epithelial differentiation (EGF, EGFR, KRT17, MAP2K6, STAT5), cell adhesion (CLDN5, CLDN8, CTNNAL1, MCAM, MUC1, PECAM1) and angiogenesis (ANGPT2, ANGPTL1, ANGPTL2, ANGPTL4, FGFR1, FIGF, TIE1) were mostly down-regulated. Interestingly, tumors had a significant decrease in membrane receptors and growth factor pathway gene expression (EGFR, FGFR1, GHR, LYVE1, PDGFR, PDGFR, TGFBR, TIE1), indicating a potential independence from these proliferative stimuli. Several of the identified deregulated pathways overlap with gene expression profiles of human breast cancer. Gene expression profiling of metastatic carcinomas therefore identified complex molecular pathways and functional gene families that are deregulated during malignant progression in the tumors. This study provides new insights into canine mammary tumor metastasis and suggests that canine mammary tumors may serve as a valuable model for the human disease. 13 simple mammary carcinomas with lymph node metastases at the time of tumor resection were compared with the non-neoplastic mammary gland of the same dogs. Sufficient amounts of normal mammary gland were not available for dogs no. 1 (822) and 9 (61). In addition, one normal sample without matching tumor sample was analyzed (no. 8; 2609). All patients had no radiographically detectable pulmonary metastases at the time of tumor resection. Postoperative survival was analyzed by bi-yearly telephone interviews with the owners or the attending veterinarian. Distant metastases as the cause of death were determined postoperatively by radiographic detection of metastases (nos. 1-7, 9-12) or necropsy (nos. 13 and 14). Necropsy was not authorized by the owners of dogs nos. 1-7 and 9-12. Tissue specimens of tumors and lymph node metastases were fixed in neutral-buffered 4% formalin or snap frozen in liquid nitrogen within 15 minutes after resection and stored at -80ºC until further use. Formalin-fixed tumor tissue samples were routinely embedded in paraffin and sections of 2-μm thickness were mounted on adhesive glass slides and stained with hematoxylin and eosin. Tumors and lymph nodes were evaluated histologically independently by two board-certified pathologists, following the criteria of the WHO classification of canine mammary tumors (Misdorp et al. 1999).

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Metastatic canine mammary carcinomas can be identified by a gene expression profile that partly overlaps with human breast cancer profiles.

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Metastatic canine mammary carcinomas can be identified by a gene expression profile that partly overlaps with human breast cancer profiles.

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