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

Abstract

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.

A Statistical Analysis of Risk Factors and Biological Behavior in Canine Mammary Tumors: A Multicenter Study

“…Similarly, the breed showed a slight influence in the logistic and GBM machine learning models (<1%), corroborating the considerable divergences between studies regarding the breed as a CMT risk factor. Moreover, considering that the mutations in Breast BRCA1 and 2 genes and their protein products have been variably associated with the development of CMTs, a definitive conclusion about CMT breed-related risk should be performed in the context of genetic research [12][13][14][15].…”

“…However, considerable discrepancies exist between studies regarding the breed as a CMT risk factor. A representative case is the evaluation of familial or inherited germline mutations in Breast Cancer 1 and 2 genes (BRCA1 and BRCA2), that in women are related to an increased lifetime risk of HBC, but that led to nonspecific results in veterinary medicine [ 12 , 13 , 14 , 15 ].…”

From Conventional to Precision Therapy in Canine Mammary Cancer: A Comprehensive Review

“…Additional treatment (adjuvant therapy) can be given after the primary mammary cancer treatment (surgery) to lower the risk of developing further recurrences and metastasis. Adjuvant therapy may include chemotherapy, radiotherapy, and targeted or individualized therapy, this latest based on the specific genetic characteristics of the cancer in a patient ( 52 – 55 ).…”

Quantification of Global DNA Methylation in Canine Mammary Gland Tumors via Immunostaining of 5-Methylcytosine: Histopathological and Clinical Correlations

“…Mammary tumors are the most prevalent neoplasm in non-neutered female dogs (1) representing ∼50% of tumor diagnoses (2). The risk of developing mammary tumors is associated with hormone levels, breed susceptibility, age, diet, and obesity (3).…”