Project description:Modeling molecular changes in breast cancer with naturally occurring canine mammary tumors and cross-organism analysis enables resolution of malignancy-specific processes.
Project description:Molecular mechanisms of the canine mammary malignancy. RNA isolated from canine mammary tumours of the 3rd grade of malignancy was pooled and hybrydized on the same microarray as RNA isolated from canine mammary tumours of the 1st grade of malignancy. Based on the results the "malignancy portrait" was assessed.
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:Spontaneously occurring canine mammary cancer represents an excellent model of human breast cancer, but is greatly understudied. To better use this valuable resource, we performed whole-genome sequencing, whole-exome sequencing, RNA-seq, and/or high-density arrays on twelve canine mammary cancer cases, including seven simple carcinomas and four complex carcinomas. Canine simple carcinomas, which histologically match human breast carcinomas, harbor extensive genomic aberrations, many of which faithfully recapitulate key features of human breast cancer. Canine complex carcinomas, which are characterized by proliferation of both luminal and myoepithelial cells and are rare in human breast cancer, seem to lack genomic abnormalities. Instead, these tumors have about 35 chromatin-modification genes downregulated and are abnormally enriched with active histone modification H4-acetylation, whereas aberrantly depleted with repressive histone modification H3K9me3. Our findings indicate the likelihood that canine simple carcinomas arise from genomic aberrations, whereas complex carcinomas originate from epigenomic alterations, reinforcing their unique value. Canine complex carcinomas offer an ideal system to study myoepithelial cells, the second major cell lineage of the mammary gland. Canine simple carcinomas, which faithfully represent human breast carcinomas at the molecular level, provide indispensable models for basic and translational breast cancer research.
Project description:Molecular mechanisms of the canine mammary malignancy. RNA isolated from canine mammary tumours of the 3rd grade of malignancy was pooled and hybrydized on the same microarray as RNA isolated from canine mammary tumours of the 1st grade of malignancy. Based on the results the "malignancy portrait" was assessed. Dye-swap experiment, gene expression in the most malignant canine mammary tumours (the 3rd grade of malignancy) was compared to the less malignant tumours (1st grade of malignancy).
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:We explored the expression profile of circRNAs in canine mammary tumours using high-throughput sequencing technology. In our study, we analysed the expression profiles of 3 pairs of canine mammary tumours and their adjacent normal tissues. The total RNA was extracted, and a RNA library was constructed. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses revealed that these genes were mainly concentrated in 14 biological pathways. We selected 11 validated circRNAs and further confirmed the existence of these circRNAs by qRT-PCR. The circRNA-miRNA network diagram was constructed by using Cytoscape software. We found a total of 14851 circRNAs and 106 differentially expressed circRNAs in canine mammary tumours and their adjacent normal tissues (fold change ≥ 2, P ≤ 0.05). There were 64 upregulated circRNAs and 42 downregulated circRNAs. The main GO functions were the regulation of the regulated secretory pathway, the regulation of neurotransmitter secretion and the positive regulation of phagocytosis. Most of these pathways were related to the cGMP-PKG (cyclic guanosine monophosphate) signalling pathway, the cAMP (cyclic adenosine monophosphate) signalling pathway and the OXYTOCIN signalling pathway. CircRNAs have the function of adsorbing miRNA, similar to a sponge, and we further constructed the interaction network of circRNAs and miRNAs. The screened source genes closely related to canine mammary tumours included RYR2, PDE4D, ROCK2, CREB3L2 and UBA3. The screened circRNAs related to canine mammary tumours included chr27:26618544-26687235-, chr26:8194880-8201833+, and chr17:7960861-7967766-.In conclusion, our study uncovered circRNA expression profiles in canine mammary tumours. Moreover, some circRNAs may be used as potential biomarkers for screening dogs with high-risk canine mammary tumours.
Project description:Spontaneously occurring canine mammary cancer (MC) represents an excellent model of human breast cancer, but is greatly understudied. We performed high density arrays on 12 canine MC cases, including 7 simple carcinomas and four complex carcinomas. Simple carcinomas, which histologically match human breast carcinomas, harbor extensive genomic aberrations, many faithfully recapitulating key features of human breast cancer. Complex carcinomas, with luminal and myoepithelial cells both proliferating (which is rare in human breast cancer), appear to lack genomic abnormalities. Comparison of CNAs from canine mammary simple carcinomas and complex carcinomas
Project description:The aim of our study was to assess miRNA expression of canine mammary cancer stem cells. Three canine mammary cancer cell lines (CMT-U27, CMT-U309 and P114) were stained using Anti-Sca1 (Stem cell antigen 1) antibodies. The FACS analysis showed 0,3-1% of Sca1+ cells in each of the cell line. The cells were sorted (using FACS Aria II) as Sca1+ and Sca1- and subjected to further analysis of miRNA expression (using Agilent custom miRNA microarray).
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>