CDNA microarray profiles of canine mammary tumour cell lines reveal deregulated pathways pertaining to their phenotype
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ABSTRACT:
ORGANISM(S): Canis lupus familiaris
PROVIDER: GSE7659 | GEO | 2007/09/01
SECONDARY ACCESSION(S): PRJNA99757
REPOSITORIES: GEO
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Project description:Mammary cancer is the most common type of cancer in female dogs with a lifetime risk of over 24% when dogs are not spayed. The elucidation of the complete canine genome opens new areas for development of cancer therapies. These should be tested first by in vitro models such as cell lines. However, to date, no canine mammary cell lines have been characterized by expression profiling. In this study, canine mammary tumour cell lines with histologically distinct primary tumours of origin were characterized using a newly developed canine cDNA microarray. Comparisons of gene expression profiles showed enrichment for distinct biological pathways and were related to biological properties of the cell lines such as growth rate and in vitro tumourigenicity. Additionally, gene expression profiles of cell lines also showed correspondence to their tumour of origin. Major differences were found in Wnt, cell cycle, cytokine/Rho-GTPase, alternative complement and integrin signalling pathways. Because these pathways show an overlap at the molecular level with those found in human breast cancer, the expression profiling of spontaneous canine mammary cancer may also function as a biological sieve to identify conserved gene expression or pathway profiles of evolutionary significance that are involved in tumourigenesis. These results are the basis for further characterization of canine mammary carcinomas and development of new therapies directed towards specific pathways. In addition these cell lines can be used to further investigate identified deregulated pathways and characterize until now unannotated genes. Keywords: cell line type comparision Three canine mammary tumor cell lines (CMT) originating from benign mixed tumor (CMT-U229), primary mammary osteosarcoma (CMT-U335) and primary mammary anaplastic carcinoma (P114) were compared directly to each other in this study. Total RNA was isolated from cells grown to near confluence. In vitro transcription followed by labeling and hybridization to cDNA microarray was carried out. In a loop design of hybridization, labeled cRNA from cell lines were hybridized against each other. Statistical analysis of the log transformed normalized data was done using SAM (significance analysis of microarray) and differentially expressed genes from each experimental subset (comparison of two cell lines) were identified. Dye swaps and at least one biological replicates were included under each experimental subset (each comparision).
2007-09-01 | E-GEOD-7659 | biostudies-arrayexpress
Project description:Circulating tumor cells in the peripheral have proven to be independent prognostic factors for overall survival the monitoring of therapeutic success of human breast cancer patients. Postmortem morphologic evidence also points towards the presence of circulating tumor cells in the peripheral blood of dogs with metastatic canine mammary tumors. However, the existence of these cells has not been verified in canines in vivo and they have not been isolated and characterized due to the lack of appropriate and canine specific detection methods. In the present study a panel of 73 genes with high expression levels in canine mammary carcinoma cells and but not in peripheral blood leukocytes were identified using microarray analysis. From this panel, six mRNA markers, AGR2, ATP8B1, CRYAB, F3 and IRX3, were expressed in canine mammary carcinoma cells but not in the peripheral blood of dogs. All six RT-PCR assays, were sensitive enough detect one carcinoma cell admixed in 106 or more peripheral blood leukocytes, a common concentration of circulating tumor cells in the peripheral blood of human breast cancer patients. These five mRNA markers may therefore be used to detect canine mammary circulating tumor cells and to study their spatio-temporal presence in the peripheral blood of canine patients. Two canine mammary carcinoma cell lines, CMM115 and CMM26, and peripheral blood samples of 3 healthy dog donors were used for microarray analysis. All blood donors were female, showed no signs of infectious or inflammatory disease and did not have mammary gland tumors or any other identifiable tumors at the time of collection. Furthermore, blood cell count and blood chemistry were unremarkable in all dogs.
2011-12-10 | E-GEOD-25586 | biostudies-arrayexpress
Project description:Using microarray technology, we aim to identify genes affecting the biology of mammary tumor cancers in dogs. Canine mammary gland tumors (CMGTs) are the most common neoplasms in sexually intact female dogs. CMGTs have been suggested as a model for studying human breast cancer because of several similarities, including the relative age of onset, risk factors, incidence, histological and molecular features, biological behavior, metastatic pattern, and responses to therapy.
2018-12-26 | GSE104733 | GEO
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).
2010-12-01 | E-GEOD-22516 | biostudies-arrayexpress
Project description:<p>The identification of efficient and sensitive biomarkers for non-invasive tests is one of the major challenges in cancer diagnosis. To address this challenge, metabolomics is widely applied for identifying biomarkers that detects abnormal changes in cancer patients. Canine mammary tumors exhibit physiological characteristics identical to those in human breast cancer and serve as a useful animal model to conduct breast cancer research. Here, we aimed to provide a reliable large-scale metabolite dataset collected from dogs with mammary tumors, using proton nuclear magnetic resonance spectroscopy. We identified 55 metabolites in urine samples from 20 benign, 87 malignant, and 49 healthy control subjects. This dataset provides details of mammary tumor-specific metabolites in dogs and insights into cancer-specific metabolic alterations that share similar molecular characteristics.</p>
2022-02-24 | MTBLS2550 | MetaboLights
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.
2010-12-01 | GSE22516 | GEO
Project description:Circulating tumor cells in the peripheral have proven to be independent prognostic factors for overall survival the monitoring of therapeutic success of human breast cancer patients. Postmortem morphologic evidence also points towards the presence of circulating tumor cells in the peripheral blood of dogs with metastatic canine mammary tumors. However, the existence of these cells has not been verified in canines in vivo and they have not been isolated and characterized due to the lack of appropriate and canine specific detection methods. In the present study a panel of 73 genes with high expression levels in canine mammary carcinoma cells and but not in peripheral blood leukocytes were identified using microarray analysis. From this panel, six mRNA markers, AGR2, ATP8B1, CRYAB, F3 and IRX3, were expressed in canine mammary carcinoma cells but not in the peripheral blood of dogs. All six RT-PCR assays, were sensitive enough detect one carcinoma cell admixed in 106 or more peripheral blood leukocytes, a common concentration of circulating tumor cells in the peripheral blood of human breast cancer patients. These five mRNA markers may therefore be used to detect canine mammary circulating tumor cells and to study their spatio-temporal presence in the peripheral blood of canine patients.
2011-12-10 | GSE25586 | GEO
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.
2010-12-01 | GSE20718 | GEO
Project description:The objective of the present study was to assess the gene expression profiles of canine mammary carcinoma (in unsupervised manner) classified by pathologists as the 1st, the 2nd and the 3rd grade of malignancy and compare their molecular and pathological classifications. Our analysis showed that some pathologically distinct tumours may have similar gene expression and vice-versa. Probably that is why the patients with the same pathological type of cancer often have various outcomes and respond in a heterogenous manner to anticancer agents. The molecular classification, contrary to the pathological methods, reflects the biological processes and pathways within the tumour cell, not only the morphological features. It is also helpful in the better understanding of cancer biology (genes responsible for tumourigenesis, molecular interactions within the tumour or genes involved in specific pathways which could be a target for future therapy). 18 canine mammary tumours (6 of the 1st grade of malignancy, 6 of the 2nd grade of malignancy and 6 of the 3rd grade of malignancy) were subjected to the analysis. RNA was isolated, reverse transcribed and hybridized on cDNA microarrays. Pooled RNA from all of the tumours was used as a reference, and dye-swaps were performed. Then, the unsupervised hierarchical analysis was performed.
2013-05-31 | E-GEOD-43778 | biostudies-arrayexpress
Project description:Breast (mammary) cancers in human (BC) and canine (CMT) patients share clinical, pathological, and molecular similarities that suggest dogs may be a useful translational model. Many cancers, including BC, shed exosomes that contain microRNAs (miRs) into the microenvironment and circulation, and these may represent biomarkers of metastasis and tumor phenotype. Three normal canine mammary epithelial cell (CMEC) cultures and 5 CMT cell lines were grown in serum-free media. Exosomes were isolated from culture media by ultracentrifugation then profiled qualitatively. CMEC and CMT cell lines shed round, “cup-shaped” exosomes approximately 150-200 nm by dynamic light scattering (DLS) and immunopositive for exosomal marker CD9 using Western blot. Exosomal small RNA was deep-sequenced on an Illumina HiSeq2500 sequencer and validated by qRT-PCR. Deep-sequencing averaged ~15 million reads/sample. 338 unique miRs were detected, with 145 having > ±1.5-fold difference between one or more CMT and CMEC samples. Gene ontology analysis revealed that the upregulated miRs in this exosomal population regulate a number of relevant oncogenic networks. Several miRNAs including miR-18a, miR-19a and miR-181a were predicted in silico to target the canine estrogen receptor (ESR1α). CMEC and CMT cells shed exosomes in vitro that contain differentially expressed miRs. CMT exosomal RNA expresses a limited number of miRs that are up-regulated relative to CMEC, and these are predicted to target biologically relevant hormone receptors and oncogenic pathways. These results may inform future studies of circulating exosomes and the utility of miRs as biomarkers of breast cancer in women and dogs.
2018-08-13 | GSE116881 | GEO