Canine mammary tumors as a model for human disease (Review)

Abdelmegeed, Somaia M.; Mohammed, Sulma I.

doi:10.3892/ol.2018.8411

Cited by 132 publications

(165 citation statements)

References 143 publications

(175 reference statements)

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“…The canine model of cancer is considered an excellent model for human translation [66][67][68][69]. Thus, we employed companion canines recruited to the Western College of Veterinary Medicine at the University of Saskatchewan with treatment resistant lymphoma into our study to reveal the gene expression differences between tumors with variable treatment responsivenesses, as well as to determine the effects of metformin on cancer progression in these animals.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Anaphase Promoting Complex reverses multiple drug resistant cancer

Aranson

MacDonald-Dickinson

Davies

et al. 2020

Preprint

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Like humans, canine companions spontaneously develop lymphomas that are treated by a cocktail of chemotherapy drugs. However, canines have high rates of developing multiple drug resistance (MDR), shortened clinical timelines and easy tumor accessibility, making them excellent models to study MDR mechanisms. Previously, we used in vitro cell models to demonstrate that metformin resensitized MDR cells to chemotherapy and prevented MDR development. Here, we used metformin to understand the in vivo molecular mechanisms regulating MDR development and reversal. Metformin was added to chemotherapy in MDR canines, reducing MDR biomarkers within all tumors tested, with one canine entering remission after prior repeated relapses. We employed microarray analyses to identify molecular networks involved in MDR development and the impact of metformin treatement. Tumor sampling throughout entry to remission and subsequent relapse allowed correlation of gene expression profiles to MDR tumor behavior. We discovered that the Anaphase Promoting Complex (APC), a ubiquitin-ligase regulating cell cycle progression, was impaired in MDR samples. In vitro tests demonstrated that APC activation resensitized MDR cells to chemotherapy. The companion canine, therefore, is a powerful translational MDR model that has revealed the APC as an underlying cellular mechanism associated with treatment resistance, and a novel potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Activation of the Anaphase Promoting Complex reverses multiple drug resistant cancer

Aranson

MacDonald-Dickinson

Davies

et al. 2020

Preprint

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“…32 In mice bearing mammary tumours induced by Rastransformed 4T1 cells, overexpression of NGAL dramatically decreased primary tumour size and metastatic pulmonary nodules compared with the group without NGAL. 39 Although the dog is regarded as a comparable model for human mammary neoplastic diseases, 40 there are some discrepancies between these two species with aspects to histopathology, hormonal aetiology and tumorigenesis of breast cancers. For example, in HBC, the major histologic type is ductal carcinoma, which accounts for approximately three-quarters of all cases, 41 whereas most CMTs primarily arise in the lobular unit.…”

Section: T a B L E 3 Analysis Of Inflammatory Cells Presented In Canimentioning

confidence: 99%

Expression and the molecular forms of neutrophil gelatinase‐associated lipocalin and matrix metalloproteinase 9 in canine mammary tumours

Chen

Chang

Huang

et al. 2019

Vet Comparative Oncology

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Neutrophil gelatinase‐associated lipocalin (NGAL) is a new biomarker for renal injury. It is also involved in tumorigenesis of different human cancer types. The oncogenic role of NGAL is related to its molecular forms, and heterodimer formation with matrix metalloproteinase 9 (MMP9) promotes human breast cancer (HBC) invasion and metastasis. To date, the levels of NGAL and NGAL/MMP9 complex have not yet been explored in canine mammary tumours (CMTs). Hence, this study aimed to investigate whether NGAL and its molecular forms could be the biomarker for CMT diagnosis. To this end, expression profile of NGAL and MMP9 in mammary epithelial cells as well as in urine samples were detected. By immunohistochemistry staining, NGAL was expressed at variable levels. Unlike HBC, a significant reduction in NGAL expression was demonstrated in benign and malignant CMTs as compared with normal controls. Additionally, NGAL expression was significantly reduced in dogs with metastatic CMTs. By contrast, the mean score of MMP9 expression in ascending order was normal groups, benign, and malignant CMTs. Interestingly, analysis of the molecular form revealed the NGAL/MMP9 complex presents in most mammary tissues and urine of dogs with benign or malignant CMTs, whereas the complex was absent in samples from dogs without CMTs. In conclusion, NGAL and MMP9 are ubiquitously expressed in canine mammary epithelial cells in normal and cancerous status. However, the NGAL/MMP9 complex exclusively presents in mammary tissues and urine of dogs with tumours.

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“…p53 7 249 R249W 68 p53 5 148 S148R 68 p53 8 271 E271V 68 p53 5 175 H175A 68 p53 5 163 I163F 68 p53 7 245 G245D 68 p53 7 252 L252F 68 p53 5 180 E180X 68 p53 7 245 G245A 64 p53 5 173 V173L 64 p53 8 285 P285S 64 p53 5 129 L129F 64 p53 7 248 R248Q 64 p53 8 297 P297R 64 p53 6 213 R213X 64 BRCA2 11 669 N669D 64 BRCA2 11 801 K801Q 64 BRCA2 11 908 E908Q 62 BRCA2 11 1425 T1425P 61 BRCA2 11 1435 K1435R 62 The most frequently studied biomarker of mammary tumors is Ki-67, a nuclear, non-histone protein, which can only be detected in the cell nucleus during interphase, and during mitosis. Higher levels of Ki-67 are associated with increased chances for metastasis and poorer prognosis [69,83,84]. Another biomarker is PCNA, an auxiliary protein of DNA polymerase δ, involved in the DNA repair process, cell cycle control, chromatin assembly and in RNA transcription [69,…”

Section: Figurementioning

confidence: 99%

“…Higher levels of Ki-67 are associated with increased chances for metastasis and poorer prognosis [69,83,84]. Another biomarker is PCNA, an auxiliary protein of DNA polymerase δ, involved in the DNA repair process, cell cycle control, chromatin assembly and in RNA transcription [69,83]. PCNA expression level has a positive correlation with tumor size, histological grade of malignancy, and lymph node metastasis.…”

Section: Figurementioning

confidence: 99%

“…A further look at the important tumor suppressor and biomarker p53 again revealed that p53 mutations in the highly conserved domains of exons 5-8 are correlated to tumorigenesis and increased malignancy (Table 7) [69,73,81,83]. p53 is thought to be the most frequently mutated gene in mammary tumors [69].…”

Section: Gene Exon Codon Amino Acid Substitution Referencesmentioning

confidence: 99%

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Molecular Mechanisms of Canine Cancers

Cao¹,

Kouznetsova²,

Tsigelny³

2019

obm genet

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Cancer is the leading cause of death in dogs, and 50 percent of dogs over the age of 10 develop cancer at some point. The most common cancers in dogs include lymphoma, mast cell tumors, osteosarcoma, mammary gland tumors, and melanoma, and many of them share marked similarities with their human counterparts. Although canines are afflicted with many of the same types of cancers as humans, the genetic basis behind these cancers are not as well understood. Thus, the aim of this study is to elucidate some of the molecular mechanisms behind canine cancers. Canine lymphoma mutation patterns generally vary with the type of lymphoma afflicted-B-cell lymphomas have mutations in the alternative NF-kB pathway including MAP3K14, whereas in T-cell lymphomas the mTOR pathway in boxers and cellular metabolism genes in golden retrievers are affected. Mast cell tumors are largely traced to internal tandem duplications and deletions in the juxtamembrane domain of the proto-oncogene c-KIT. In osteosarcoma, mutations in RB1 and TP53 (especially G: C->A:T transitions in exons 4 and 5), as well as CDK4 inhibitors CDKN2A/B are common. Mammary gland tumors are associated with BRCA2 underexpression due to reading frame shift and mutations in BRC repeat 3. Lastly, deletion or underexpression of p16 and PTEN and altered expression of cell-cell adhesion molecules are common factors in the development of melanoma. The genes identified were then studied to identify more key amino acid mutations that changed protein products and promoted tumorigenesis. Genes that altered expression levels of proteins were analyzed separately. Both sets of candidate genes were then analyzed with the Database for Annotation, Visualization, and Integrated Discovery (DAVID) in order to elucidate the molecular pathways involved in canine cancers and identify more genes possibly involved in tumorigenesis. The proposition of this review is that treatments for both canine and human cancers would be enhanced by comparative genomic studies.

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Canine mammary tumors as a model for human disease (Review)

Cited by 132 publications

References 143 publications

Activation of the Anaphase Promoting Complex reverses multiple drug resistant cancer

Activation of the Anaphase Promoting Complex reverses multiple drug resistant cancer

Expression and the molecular forms of neutrophil gelatinase‐associated lipocalin and matrix metalloproteinase 9 in canine mammary tumours

Molecular Mechanisms of Canine Cancers

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