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.

中文翻译：

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犬乳腺肿瘤中BRCA2的突变及其在临床治疗中的靶向潜力。

狗随着年龄的增长会自发地发展癌症，而特定品种的风险则是遗传学上的差异。据报道，在完整的母犬中，乳腺肿瘤是最常见的肿瘤。它们在某些犬种中的高流行提示其遗传成分，在人类家族性乳腺癌中就是这种情况，而在与BRCA2相关的癌症中则明显。然而，BRCA2在犬癌发病机理中的分子遗传学仍在研究中。犬BRCA2的遗传变异包括单核苷酸多态性，插入和缺失。已显示在肿瘤腺体样品中BRCA2水平降低，这表明BRCA2的低表达有助于狗的乳腺肿瘤发展。此外，BRCA2基因的特定变异会影响RAD51的结合强度，严重损坏了BRCA2-RAD51的固定装置，并进一步引发了有缺陷的维修。在人类中，临床前和临床数据揭示了BRCA2突变与PARP抑制之间的合成致死性相互作用。尽管PARP抑制剂还与许多副作用和获得性耐药有关，但它们已成功用于提高化学疗法和放射疗法的敏感性。犬类患者的癌症治疗可能会受益于化学敏感性和放射敏感性的提高，因为他们的癌症治疗方案通常只包括低剂量的药物或放射线。早期调查显示犬尼泊利布具有耐受性。PARP抑制剂还意味着更高的治疗成本，因此不太可能被宠物主人接受。我们总结了犬BRCA2基因改变及其与乳腺肿瘤相关性的当前证据。通过使用PARP抑制剂，犬BRCA2基因的突变具有在临床治疗中的潜力。但是，在兽医临床实践中引入PARP抑制剂之前，需要进一步的研究。