Abstract
Breast cancer is the most prevalent tumor type among women and female dogs. Tumor malignancy is characterized by the epithelial-to-mesenchymal transition (EMT) which leads to the metastasis formation. The inhibition of angiotensin II type I receptor (AGTR1) by an antagonist such as losartan can suppress angiogenesis, consequently contributing to the metastasis control. The aim of this study was to analyze the capacity of losartan and AGTR-1 gene edition to modulate the EMT process in triple negative/metastatic mammary tumor cells, compared to existing treatment protocols such as carboplatin. The cell lines CF41.Mg and MDA-MB-468, were cultured and treated with carboplatin, losartan, or submitted to AGTR-1 gene edition by CRISPR/Cas9. EMT markers and PARP-1 protein and gene expression were evaluated by immunofluorescence or immunocytochemistry and qRT-PCR, respectively. Cell migration capacity was also evaluated. For CF41.Mg and MDA-MB-468 cell lines, there was an increase in E-cadherin and a decrease in N-cadherin and PARP-1 protein and gene expression after treatment with carboplatin, losartan, both in combination and after AGTR-1 gene edition. There was a decrease in VEGF and PARP-1 protein and gene expression after AGTR-1 gene edition. Moreover, in both lines, reduction in invasion rate was observed after all treatments. Our data suggest that losartan and the gene edition of AGTR-1 by CRISPR/Cas9 were able to block the DNA repair and control the EMT process, such as carboplatin. The results in the canine species are unprecedented, as there are no data in the literature that demonstrate the action of losartan in this tumor type.
Highlights
Breast cancer (BC) is the most frequent type of cancer among women; this type of tumor ranks second among causes for cancer related death in women
It is not clear the mechanism of action of platinum agents, but deoxyribonucleic acid (DNA) adducts are formed [22]; in this way we added losartan to the treatment to control the generation of epithelial-to-mesenchymal transition (EMT) process and compared its action with the results achieved after treatment with carboplatin, which is the compound used worldwide for the treatment of breast cancer
The cells were imaged by confocal microscopy and subsequent immunofluorescence-labelling we added losartan to the treatment to control the generation of EMT process and compared its action with the results achieved after treatment with carboplatin, which is the compound used worldwide for the treatment of breast cancer
Summary
Breast cancer (BC) is the most frequent type of cancer among women; this type of tumor ranks second among causes for cancer related death in women. Several genetic and environmental factors, especially those co-existing, increase the risk of occurrence, morbidity, and recurrence of BC. Other well-recognized and documented risk factors include age and familial genetic predisposition [2,3]. Breast tumors are described as the most frequent neoplasm in female dogs. Dogs develop cancer spontaneously with age, with genetic differences related to race-specific risk. The high prevalence in some breeds suggests a genetic component, as it occurs in familial human breast cancer [4]. The most effective treatment in breast cancer is surgical excision, due to the high incidence of metastases in this type of tumor, surgery alone is not efficient in all canine patients [5]
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