Expressão de Nrf2 nas Neoplasias Mamárias de Cadelas e sua correlação com fatores Prognósticos e sobrevida

Abstract

Given the high frequency of mammary cancer in female dogs, there is an increasing search for improved prognostic and therapeutic indications in veterinary oncology practice. Thus, prognostic factors in mammary neoplasms are the subject of various studies. Among these factors, the nuclear transcription factor erythroid 2-related factor 2 (NRF2) stands out in human oncology. It regulates the cellular antioxidant system and acts as a suppressor, promoter, or both in carcinogenesis. However, there is a scarcity of studies related to this transcription factor in veterinary medicine. In this context, the objective was to evaluate the expression of NRF2 in mammary neoplasms of female dogs, its correlation with tumor progression, classic prognostic factors (clinical staging, tumor size, and histopathological grade), and survival. Forty-four samples of mammary glands from female dogs of different breeds and ages were analyzed, classified into: control group (n=6) (mammary glands without histological alterations), benign neoplasms (n=8), and malignant neoplasms (n=30). The samples were obtained from the Veterinary Pathology Laboratory of HOSPMEV-UFBA and a private laboratory in the city of Salvador between 2018 and 2022. Clinical records and histopathological reports were reviewed, and data regarding tumor size, clinical staging, diagnosis, histopathological grade, and survival time were collected. Based on the histological and clinical diagnosis, the following tumor subgroups were formed for qualitative and quantitative evaluation, using the histochemical score (H-score) of NRF2 expression and the proliferation index (Ki-67): benign mixed tumors (BMT) (n=5), simple adenomas (n=2), adenomyoepithelioma (n=1), simple carcinomas (n=6), carcinoma in mixed tumors (CMT) (n=14), further subdivided into grade I (n=7) and grades II and III (n=7), carcinosarcomas (n=4), and malignant adenomyoepitheliomas (n=6). The results of NRF2 expression indicated predominantly cytoplasmic staining and a decrease in the H score with an increase in the criteria of tumor malignancy. The H-score of the malignant tumor group differed only from the control group (p<0.001). When comparing the tumor subgroups, it was observed that simple carcinomas had higher immunohistochemical expression than simple adenomas, unlike mixed tumors, where the expression was higher in benign tumors compared to carcinoma in mixed tumors and carcinosarcomas. Animals with higher H-scores showed longer survival, while proliferative capacity was higher in tumors with NRF2 expression equal to or less than 156.5, with a strong negative correlation and significant association (r= -0.698; p=0.001). The evaluation of clinical and pathological parameters in malignant neoplasms, in the univariate analysis, indicated a significant association and negative correlation of the H-score with Ki-67, clinical staging, and tumor size, whereas in the multivariate analysis, there was only a correlation with Ki-67. These collectively evaluated results did not confer significant clinical value to NRF2; thus, it is not an independent prognostic factor in female dogs with mammary tumors.