A monograph proposing the use of canine mammary tumours as a model for the study of hereditary breast cancer susceptibility genes in humans

Goebel, Katie; Merner, Nancy D.

doi:10.1002/vms3.61

Cited by 19 publications

(21 citation statements)

References 48 publications

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“…In regards to dogs breeds, a high incidence of mammary neoplasms in mongrel dogs and poodle breed have been frequently reported by other studies, confirming the importance of these findings in different dog populations. In the comparative oncology field, a work proposed the study of dog pedigrees as an alternative to reducing genetic heterogeneity in molecular researches of human breast cancer susceptibility, since artificial selection has resulted in elevated homogeneity …”

Section: Discussionmentioning

confidence: 99%

Common germline haplotypes and genotypes identified in BRCA2 exon 11 of dogs with mammary tumours and histopathological analyses

Maués

El-Jaick

Costa

et al. 2018

Vet Comparative Oncology

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Funding informationCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) of the Brazilian Ministry of Education The canine BRCA2 is a tumor supressor gene which encodes the BRCA2 protein, involved in DNA repair through interaction with the RAD51 recombinase. This process is mediated by eigth BRC repeats that are encoded by BRCA2 exon 11. Two variants corresponding to human mutations in human BRC3 repeat have been reported in canine BRC3 repeat. In addition, other variants have also been described in canine BRCA2 exon 11. Considering the importance of polymorphisms in human BRCA2 to breast cancer development, this study aimed to investigate the frequency of variants in BRCA2 exon 11 in 48 blood and tissue DNA samples from bitches with canine mammary tumors (CMT), as well as, to analyze tumor stage and histopathological features. Seven Single Nucleotide Polymorphisms (SNPs) were identified, three of which were evaluated as possibily or probably deleterious variant.Interestingly, almost all the 22 mammary tumors (except one) which presented a clinical staging equal to or greater than III carried at least one mutant allele of these three variants.Besides that, no statistically significant correlation was observed between any of the reported SNPs in heterozygosis or homozygosis and either dogs data (such as breed, age or disease stage) or mammary tumors histopathological characteristics. A total of 97.9% of bitches had one to three polymorphisms of the seven identified in this study, which suggests a possibly correlation between the canine BRCA2 exon 11 polymorphisms and mammary carcinogenesis. K E Y W O R D SBRCA2, breast cancer, canine, carcinogenesis, RAD51

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Section: Discussionmentioning

confidence: 99%

Common germline haplotypes and genotypes identified in BRCA2 exon 11 of dogs with mammary tumours and histopathological analyses

Maués

El-Jaick

Costa

et al. 2018

Vet Comparative Oncology

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“…Furthermore, canine cancers share evolutionarily conserved genomic changes that are found in humans 21 . Interestingly, several of the human cancer predisposition genes have been discovered in the constitutional (germline) DNA of dogs with cancer, including mutations in BRCA1, BRCA2, and p53 [21][22][23][24] . Like its human counterpart, canine p53 is also found to be mutated in several types of dogs tumors (including osteosarcoma and mammary tumors) 25 .…”

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confidence: 99%

A dog oviduct-on-a-chip model of serous tubal intraepithelial carcinoma

Ferraz

Nagashima

Venzac

et al. 2020

Sci Rep

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Ovarian cancer is the fifth cause of cancer-related mortality in women, with an expected 5-year survival rate of only 47%. High-grade serous carcinoma (HGSC), an epithelial cancer phenotype, is the most common malignant ovarian cancer. It is known that the precursors of HGSC originate from secretory epithelial cells within the Fallopian tube, which first develops as serous tubal intraepithelial carcinoma (STIC). Here, we used gene editing by CRISPR-Cas9 to knock out the oncogene p53 in dog oviductal epithelia cultured in a dynamic microfluidic chip to create an in vitro model that recapitulated human STIC. Similar to human STIC, the gene-edited oviduct-on-a-chip, exhibited loss of cell polarization and had reduced ciliation, increased cell atypia and proliferation, with multilayered epithelium, increased Ki67, PAX8 and Myc and decreased PTEN and RB1 mRNA expression. This study provides a biomimetic in vitro model to study STIC progression and to identify potential biomarkers for early detection of HGSC.Ovarian high-grade serous carcinoma (HGSC) and tubal epithelium share similar morphology, immuno-phenotype, and gene and protein expression patterns 1-3 . Transformed human Fallopian tube stem cells give rise to tumors that recapitulate the morphology and gene expression of HGSC after injection into immune-deficient mice 4 . Furthermore, most Fallopian tube cancer lesions (96%), such as serous tubal intraepithelial carcinoma (STIC), are marked by mutant p53, as are their metastatic form HGSC 5,6 . Past research on HGSC has used human tumor cells, but it has been hampered by the inefficiency of platting and sub-culturing of Fallopian tube epithelium, a process that involves a long period of fibroblast contamination reduction 7 . Furthermore, these processes result in the selection of specific cell populations, which lack tumor molecular characteristics, mutations and intra-patient heterogeneity 7-9 . Human HGSC has also been studied using patient-derived xenografts, but these technologies are time and resource-consuming, are poorly suitable for genetic manipulation and drug screening, and experience rapid mouse-specific tumor evolution 7 .Alternatively, knocked-out animals are used, being rodents the most used genetic engineered models of HGSC 10-14 . However, data generated from rodents are not readily translated to the human. First, the mouse does not naturally develop HGSC 15,16 . Secondly, genetically engineered and syngeneic mouse models may not exhibit genetic alterations relevant to human HGSC and, in many instances, may be driven by inappropriate regulatory sequences and promoters 15,16 . Third, cancer phenotypes can vary depending on the mouse strain used to create the cancer model 16 . Fourth, infertility resulting from ovarian tumors has limited the production of transgenic mouse models for ovarian cancer 17 . Nevertheless, the recent advances of the CRISPR-Cas9 system for knocking in and out target genes might offer the same opportunity of gene editing large mammalian species and can specifically increas...

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“…There are many shared features of human and canine breast cancer. As in women and unlike rodent models, the mammary glands are the most common site of cancer in unspayed female dogs 12,13 . In addition, canine models develop invasive mammary tumors faster and have shorter survival times compared to humans, making them an excellent model to study human breast cancer 12,14 .…”

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confidence: 99%

DNA methylation landscape of triple-negative ductal carcinoma in situ (DCIS) progressing to the invasive stage in canine breast cancer

Beetch

Harandi-Zadeh

Yang

et al. 2020

Sci Rep

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triple-negative breast cancer (tnBc) is a subtype of breast cancer unresponsive to traditional receptortargeted treatments, leading to a disproportionate number of deaths. invasive breast cancer is believed to evolve from non-invasive ductal carcinoma in situ (DciS). Detection of triple-negative DciS (tn-DciS) is challenging, therefore strategies to study molecular events governing progression of pre-invasive tn-DciS to invasive tnBc are needed. Here, we study a canine tn-DciS progression and investigate the DnA methylation landscape of normal breast tissue, atypical ductal hyperplasia (ADH), DciS and invasive breast cancer. We report hypo-and hypermethylation of genes within functional categories related to cancer such as transcriptional regulation, apoptosis, signal transduction, and cell migration. DnA methylation changes associated with cancer-related genes become more pronounced at invasive breast cancer stage. Importantly, we identify invasive-only and DCIS-specific DNA methylation alterations that could potentially determine which lesions progress to invasive cancer and which could remain as pre-invasive DciS. changes in DnA methylation during tn-DciS progression in this canine model correspond with gene expression patterns in human breast tissues. this study provides evidence for utilizing methylation status of gene candidates to define late-stage (DCIS and invasive), invasive stage only or DciS stage only of tn-DciS progression. Breast cancer is classified into subtypes based on the expression of growth factor receptors including the estrogen receptor (ER), the progesterone receptor (PR), and the receptor for human epidermal growth factor (HER-2) 1. Growth of breast tumors expressing any of these receptors may be controlled effectively by treatment in the adjuvant setting with receptor-targeted drugs 2. However, breast tumors that do not express any of these receptors have no known effective adjuvant treatment capable of controlling tumor growth. Such tumors are referred to as triple-negative breast cancers (TNBC) and are the most aggressive and lethal of all breast malignancies 2. TNBC accounts for 15% of breast cancer cases and a disproportionate percentage of breast cancer deaths among women 3. It has been shown that patients with TNBC have poor prognosis and shorter median time to relapse compared to patients with other subtypes of breast cancer 4. Ductal carcinoma in situ (DCIS) is defined as a non-invasive overgrowth of cells characterized by high proliferation within the breast ductal system. Studies suggest that triple-negative DCIS (TN-DCIS), a rare type of DCIS, is a precursor stage of invasive breast cancer 5,6. Therefore, early detection of TN-DCIS is important in preventing breast cancer cases that may progress to triple negative invasive carcinoma. However, TN-DCIS is challenging to detect at early stage in humans 7. Despite efforts to use immunohistochemistry to measure receptor expression in scientific studies of human DCIS tissues, detection of receptor status, including ER, is not routi...

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A monograph proposing the use of canine mammary tumours as a model for the study of hereditary breast cancer susceptibility genes in humans

Cited by 19 publications

References 48 publications

Common germline haplotypes and genotypes identified in BRCA2 exon 11 of dogs with mammary tumours and histopathological analyses

Common germline haplotypes and genotypes identified in BRCA2 exon 11 of dogs with mammary tumours and histopathological analyses

A dog oviduct-on-a-chip model of serous tubal intraepithelial carcinoma

DNA methylation landscape of triple-negative ductal carcinoma in situ (DCIS) progressing to the invasive stage in canine breast cancer

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