Multiplex Gene Expression Profiling of 16 Target Genes in Neoplastic and Non-Neoplastic Canine Mammary Tissues Using Branched-DNA Assay

Ripoli, Florenza Lüder; Hammer, Susanne Conradine; Mohr, Annika; Willenbrock, Saskia; Hewicker‐Trautwein, M.; Brenig, Bertram; Escobar, Hugo Murua; Nolte, Ingo

doi:10.3390/ijms17091589

Cited by 4 publications

(3 citation statements)

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“…HR is essential for DNA double‐strand break repair and cancer prevention (Hodgson & Turashvili, 2020 ; O'kane et al., 2017 ; Trenner & Sartori, 2019 ). Studies have shown a relationship between mutations in the BRCA2 (Borge et al., 2011 ; Enginler et al., 2014 ; Kaszak et al., 2018 ; Lüder Ripoli et al., 2016 ; Ozmen et al., 2017a ) and RAD51 genes and CMT (Canadas et al., 2018 ; Ozmen et al., 2017b ; Uemura et al., 2019 ). The significance of PALB2 mutations in BCs is well known and is routinely monitored (Cock‐Rada et al., 2018 ; Schroeder et al., 2015 ; Slavin et al., 2015 ; Yao et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis of PALB2 gene WD40 domain in canine mammary tumour patients

Çıldır,

Özmen,

Kul

et al. 2024

Veterinary Medicine & Sci

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BackgroundDNA repair mechanisms are essential for tumorigenesis and disruption of HR mechanism is an important predisposing factor of human breast cancers (BC). PALB2 is an important part of the HR. There are similarities between canine mammary tumours (CMT) and BCs. As its human counterpart, PALB2 mutations could be a predisposing factor of CMT.ObjectivesIn this study, we aimed to investigate the impacts of PALB2 variants on tumorigenesis and canine mammary tumor (CMT) malignancy.MethodsWe performed Sanger sequencing to detect germline mutations in the WD40 domain of the canine PALB2 gene in CMT patients. We conducted in silico analysis to investigate the variants, and compared the germline PALB2 mutations in humans that cause breast cancer (BC) with the variants detected in dogs with CMT.ResultsWe identified an intronic (c.3096+8C>G) variant, two exonic (p.A1050V and p.R1354R) variants, and a 3′ UTR variant (c.4071T>C). Of these, p.R1354R and c.4071T>C novel variants were identified for the first time in this study. We found that the p.A1050V mutation had a significant effect. However, we could not determine sufficient similarity due to the differences in nucleotide/amino acid sequences between two species. Nonetheless, possible variants of human sequences in the exact location as their dog counterparts are associated with several cancer types, implying that the variants could be crucial for tumorigenesis in dogs. Our results did not show any effect of the variants on tumor malignancy.ConclusionsThe current project is the first study investigating the relationship between the PALB2 gene WD40 domain and CMTs. Our findings will contribute to a better understanding of the pathogenic mechanism of the PALB2 gene in CMTs. In humans, variant positions in canines have been linked to cancer‐related phenotypes such as familial BC, endometrial tumor, and hereditary cancer predisposition syndrome. The results of bioinformatics analyses should be investigated through functional tests or case‐control studies.

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Section: Discussionmentioning

confidence: 99%

Genetic analysis of PALB2 gene WD40 domain in canine mammary tumour patients

Çıldır,

Özmen,

Kul

et al. 2024

Veterinary Medicine & Sci

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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]. However, in cases where a lower expression of BRCA2 is observed, what are the mechanisms triggering the tumor development?…”

Section: Main Textmentioning

confidence: 98%

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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“…Like women, breast tumors are the most common tumors in female dogs. Multi-branched DNA (b-DNA) analysis of canine breast tumor frozen specimens revealed that PFDN5 expression was significantly lower in malignant tumors [70,71]. PFDN5 gene somatic cell deletion is more common in canine breast cancer and it is common and closely related to high Ki-67 scores [72,73], indicating that down-regulation or deletion of PFDN5 expression has a very important role in the development of canine breast cancer.…”

Section: The Role Of the Prefoldin Subunits In Other Speciesmentioning

confidence: 99%

The functions and mechanisms of prefoldin complex and prefoldin-subunits

et al. 2020

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The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins. Prefoldin plays a crucial role in the pathogenesis of common neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and Huntington's disease). The important role of prefoldin in emerging fields (such as nanoparticles, biomaterials) and tumors has attracted widespread attention. Also, each of the prefoldin subunits has different and independent functions from the prefoldin complex. It has abnormal expression in different tumors and plays an important role in tumorigenesis and development, especially c-Myc binding protein MM-1. MM-1 can inhibit the activity of c-Myc through various mechanisms to regulate tumor growth. Therefore, an in-depth analysis of the complex functions of prefoldin and their subunits is helpful to understand the mechanisms of protein misfolding and the pathogenesis of diseases caused by misfolded aggregation.

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Multiplex Gene Expression Profiling of 16 Target Genes in Neoplastic and Non-Neoplastic Canine Mammary Tissues Using Branched-DNA Assay

Cited by 4 publications

References 45 publications

Genetic analysis of PALB2 gene WD40 domain in canine mammary tumour patients

Genetic analysis of PALB2 gene WD40 domain in canine mammary tumour patients

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

The functions and mechanisms of prefoldin complex and prefoldin-subunits

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