Reduced canine BRCA2 expression levels in mammary gland tumors

Yoshikawa, Yasunaga; Morimatsu, Masami; Ochiai, Kazuhiko; Ishiguro‐Oonuma, Toshina; Wada, Seiichi; Orino, Koichi; Watanabe, Kiyotaka

doi:10.1186/s12917-015-0483-9

Cited by 21 publications

(33 citation statements)

References 29 publications

(32 reference statements)

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“…Thus, Yoshikawa et al later investigated the mRNA levels of BRCA2 in canine mammary tumor samples compared to mammary gland samples and found a significantly reduced level in the tumor samples, suggesting that low expression of BRCA2 contributes to mammary tumor development in dogs [23]. In contrast, a study conducted by Ripoli et al did not show a significant difference in BRCA2 gene expression levels in between canine healthy tissue, malignant and benign tumors from fresh frozen samples [34].…”

Section: Main Textmentioning

confidence: 99%

“…Thus, certain biomarkers of canine mammary tumors have been discovered and investigated in order to improve early detection of the tumors [20]. Among other gene mutations, mutations in the BRCA1/2 genes (Breast Cancer 1 and 2; their protein products are commonly called breast cancer type 1 or 2 susceptibility protein) have been reportedly associated with the development of mammary tumors in dogs [21][22][23]. Apart from being useful as biomarkers, BRCA1/2 have been also investigated as potential treatment targets [24].…”

Section: Introductionmentioning

confidence: 99%

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Mutations of BRCA2 in canine mammary tumors and their targeting potential in clinical therapy

2020

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Dogs develop cancer spontaneously with age, with breed-specific risk underlying differences in genetics. Mammary tumors are reported as the most frequent neoplasia in intact female dogs. Their high prevalence in certain breeds suggests a genetic component, as it is the case in human familial breast cancer, distinctly in BRCA2-associated cancers. However, the molecular genetics of BRCA2 in the pathogenesis of canine cancer are still under investigation. Genetic variations of canine BRCA2 comprised single nucleotide polymorphisms, insertions and deletions. The BRCA2 level has been shown to be reduced in tumor gland samples, suggesting that low expression of BRCA2 is contributing to mammary tumor development in dogs. Additionally, specific variations of the BRCA2 gene affect RAD51 binding strength, critically damage the BRCA2-RAD51 binding and further provoke a defective repair. In humans, preclinical and clinical data revealed a synthetic lethality interaction between BRCA2 mutations and PARP inhibition. PARP inhibitors are successfully used to increase chemo-and radiotherapy sensitivity, although they are also associated with numerous side effects and acquired resistance. Cancer treatment of canine patients could benefit from increased chemo-and radiosensitivity, as their cancer therapy protocols usually include only low doses of drugs or radiation. Early investigations show tolerability of iniparib in dogs. PARP inhibitors also imply higher therapy costs and consequently are less likely to be accepted by pet owners. We summarized the current evidence of canine BRCA2 gene alterations and their association with mammary tumors. Mutations in the canine BRCA2 gene have the potential to be exploited in clinical therapy through the usage of PARP inhibitors. However, further investigations are needed before introducing PARP inhibitors in veterinary clinical practice.

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Section: Main Textmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutations of BRCA2 in canine mammary tumors and their targeting potential in clinical therapy

2020

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“…In contrast to osteosarcoma, which affects large dog breeds, mammary tumors ( Figure 15) tend to occur in the achondroplastic Dachshund and a number of small breeds including the Poodle, Maltese Terrier, Cocker Spaniel, Yorkshire Terrier and the Beagle. Conserved tumorigenesis orthologs implicated in this tumor type include CTNNB1 and PTEN [59] while least conserved orthologs associated with canine mammary tumors include BRCA1 [4] AND [60], BRCA2 [61], MUC1 [62], and KLF4 [63]. Interestingly, tumor associated macrophages (TAMs) have been implicated in modulating tumor invasion and metastasis in this cancer type [64].…”

Section: Discussionmentioning

confidence: 99%

Leveraging Naked Mole Rat (Heterocephalus glaber) Comparative Genomics to Identify Canine Genes Modulating Susceptibility to Tumorigenesis and Cancer Phenotypes

Irizarry¹,

Punt²

2015

J Veterinar Sci Technol

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We utilized a comparative genomics approach to analyze a core set of tumorigenesis orthologs among human, mouse, dog and naked mole rat. The analysis identified cancer orthologs that are both conserved and divergent between dog and the cancer resistant species naked mole rat. These tumorigenesis orthologous are associated with phenotypes that modulate cancer susceptibility, cardiac development, craniofacial development, brain development, skeletal development, and immune function, to name a few. This bioinformatics approach employed a variety of literature mining tools to further uncover relationships between the tumorigenesis orthologs. Together, these results shed light on the relationship between breed formations, breed associated morphological traits and breed associated susceptibility to tumorigenesis. These findings support the use of a comparative genomic analysis between species with dramatically different disease phenotypes as a gene discovery tool. A total of 146 proteins coding SNPs were identified in these tumorigenesis orthologs representing missense variations, frame shift variations and nonsense variations. The genes identified in this study can serve as a list of candidates for subsequent laboratory and clinical study. Furthermore, the identification of SNPs impacting the primary structure of the tumorigenesis orthologs may provide clues about the basis of cancer susceptibility between dog breeds.

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“…It binds to Rad51 recombinase through interaction with eight BRC repeats, and the complex repairs DNA damage through homologous recombination repair ( Figure 4) [72,[78][79][80]. In one study, it was found that mammary tumors express less BRCA2 than normal mammary glands, which would explain how mutations causing breast cancer might arise [72]. However, the cause for the underexpression is unclear-there were no mutations in the promoter that might affect transcription levels.…”

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confidence: 99%

“…However, the cause for the underexpression is unclear-there were no mutations in the promoter that might affect transcription levels. The study discovered two BRCA2 splice variants, one of which induced a shift in reading frame that lead to nonsense-mediated RNA decay and thus underexpression [72]. In addition, there were many single nucleotide polymorphisms in exon 11 of BRCA2 (Table 7) and a high frequency of genetic variation at two "hot spots" (A511C and A2414G) in many tumors that could have led to BRCA2 underexpression [79,81,82].…”

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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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Reduced canine BRCA2 expression levels in mammary gland tumors

Cited by 21 publications

References 29 publications

Mutations of BRCA2 in canine mammary tumors and their targeting potential in clinical therapy

Mutations of BRCA2 in canine mammary tumors and their targeting potential in clinical therapy

Leveraging Naked Mole Rat (Heterocephalus glaber) Comparative Genomics to Identify Canine Genes Modulating Susceptibility to Tumorigenesis and Cancer Phenotypes

Molecular Mechanisms of Canine Cancers

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