Avaliação de biomarcadores associados ao prognóstico de tumores mamários em cadelas
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2025-01-29
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Bustamante Filho, Ivan Cunha
Banca
Fernandes, Cristina Gevehr
Cassali, Geovanni Dantas
Martins, Maria Isabel Mello
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Os tumores mamários caninos (TMC) são as neoplasias mais comuns em cadelas, sendo que entre 35% a 85% dessas lesões são malignas. A incidência desses tumores em cadelas é três vezes maior do que em mulheres, embora o processo seja semelhante. Os TMC ocorrem com mais frequência entre 8 e 11 anos de idade e, embora a etiologia exata seja desconhecida, fatores hormonais, nutricionais e genéticos são considerados de risco. Os tipos mais agressivos incluem carcinoma tubular, sólido, pleomórfico lobular, micropapilar e carcinossarcoma. A combinação de carcinomas com áreas sólidas ou micropapilares pode reduzir o tempo de sobrevida, destacando a importância do exame histopatológico detalhado. A mastectomia é o tratamento padrão, exceto em casos metastáticos ou lesões inflamatórias. O prognóstico baseia-se em fatores como avaliação clínica, tamanho da lesão, metástases detectadas por exames de imagem e resultados histopatológicos. O uso de biomarcadores específicos é essencial para confirmar o diagnóstico, avaliar o prognóstico e orientar o tratamento, auxiliando na detecção de metástases ocultas e na monitorização da resposta terapêutica. Neste contexto, o objetivo desse trabalho foi identificar e quantificar a expressão de genes e de proteínas em biópsias tumorais e em tecidos mamários saudáveis, correlacionando-os com classificações clínicas e histopatológicas para avaliar seu potencial como fatores prognósticos na progressão do TMC. Para o estudo epidemiológio acompanhamos 21 casos de TMC submetidos à remoção cirúrgica, durante um período de 24 meses. Fatores como raça, idade, tamanho do tumor, estágio de TNM e resultados histopatológicos foram avaliados. O estudo constatou que 77% das neoplasias analisadas eram tumores malignos. O tamanho do tumor foi correlacionado com o grau histológico, e o estágio TNM eleveado foi associado à baixa sobrevida global. Múltiplos tumores foram mais comuns em cadelas mais velhas. A ovariohisterectomia foi considerada um fator protetor para cadelas com tumores malignos. Os carcinomas em tumores mistos foram as neoplasias malignas mais prevalentes, seguidos do carcinoma tubular e dos carcinossarcomas. Este estudo fornece informações sobre a TMC e enfatiza a importância de conhecer fatores como tamanho do tumor, grau histológico e idade do cão. A intervenção oportuna e os exames de acompanhamento podem impactar significativamente no prognóstico, e deve-se considerar a ovariohisterectomia como uma opção de tratamento. Além disso, fez o estudo da expressão dos genes EGFR e HER-2 em 125 amostras de CMT. Os resultados mostraram que o mRNA do EGFR está em níveis mais elevados em alguns subtipos de tecidos CMT do que em tecidos saudáveis. Os níveis de expressão gênica de EGFR em tumores foram correlacionados com parâmetros clínicos associados ao aumento de malignidade, como tamanho tumoral aumentado, grau e tipos histológicos mais agressivos (carcinossarcoma, carcinoma micropapilar e adenomioefitelioma maligno). Semelhante a estes resultados, a expressão de HER-2 foi maior no carcinoma micropapilar e no carcinossarcoma. Sugerindo o envolvimento de EGFR e HER-2 na invasão tumoral e pior prognóstico. Com base nestes resultados, pode-se supor que estes receptores desempenham papéis diferentes em tecidos saudáveis e tumores malignos. Nossos achados sugerem que os receptores EGFR e HER-2 parecem desempenhar um papel na proliferação de tecidos da glândula mamária em cadelas e estão associados à agressividade biológica dos tumores e, portanto, podem ser potenciais alvos terapêuticos também na TMC. Além disso, realizou-se o estudo através da técnica de LC-MS/MS da expressão proteica de 26 amostras de tecido mamário de cadelas (20 TMC e 6 controles). Nesse estudo foram identificadas as proteínas mais abundantes em TMC (Transforming acidic coiled-coil, Proteasome subunit beta, Programmed cell death protein 2, Protein S100A2, Protein S100A9, Rho guanine nucleotide exchange factor 17, Phospholipase A and acyltransferase, A-kinase anchoring protein 6, Galectin and Ketimine reductase mu-crystallin. Essas proteínas com maior abundância nas amostras de TMC sem mostram como potenciais biomarcadores. Dadas as aparentes semelhanças entre TMC e tumores de mama em mulheres (TMH), é possível que tais dados também possam ser valiosos no diagnóstico e prognóstico do TMH.
Canine mammary tumors (CMT) are the most common neoplasms in dogs, with between 35% and 85% of these lesions being malignant. The incidence of these tumors in female dogs is three times higher than in human, although the process is similar. CMT occur most frequently between 8 and 11 years old and, although the exact etiology is unknown, hormonal, nutritional and genetic factors are considered risk factors. The most aggressive types include tubular carcinoma, solid carcinoma, pleomorphic lobular carcinoma, micropapillary carcinoma, and carcinosarcoma. The combination of carcinomas with solid or micropapillary areas can reduce survival time, highlighting the importance of detailed histopathological examination. Mastectomy is the standard treatment except in metastatic cases or inflammatory lesions. The prognosis is based on factors such as clinical evaluation, size of the lesion, metastases detected by imaging tests and histopathological results. The use of specific biomarkers is essential to confirm the diagnosis, evaluate the prognosis and to guide treatment, helping to detect occult metastases and monitor the therapeutic response. In this context, the objective of this work was to identify and quantify the expression of genes and proteins in tumor biopsies and healthy breast tissues, correlating them with clinical and histopathological classifications to evaluate their potential as prognostic factors in the progression of CMT. For the epidemiological study, we analyzed 21 cases of CMT that underwent surgical removal, with these animals being monitored during 24 months. Factors such as breed, age, tumor size, TNM stage, and histopathological results were evaluated. The study found that 77% of the neoplasms analyzed were malignant tumors. Tumor size was correlated with histological grade, and high-level TNM stage was associated with poor overall survival. Multiple tumors were more common in older dogs. Ovariohysterectomy was considered a protective factor for bitches with malignant tumors. Carcinomas in mixed tumors were the most prevalent malignant neoplasms, followed by tubular carcinoma and carcinosarcomas. This study provides information about CMT and emphasizes the importance of knowing factors such as tumor size, histological grade and age of the dog. Timely intervention and follow-up examinations can significantly impact prognosis, and ovariohysterectomy should be considered as a treatment option. In addition, we studied the expression of the EGFR and HER-2 genes in 125 CMT samples. The results show that EGFR mRNA is at higher levels in some CMT tissue subtypes than in healthy tissues. EGFR gene expression levels in tumors were correlated with clinical parameters associated with increased malignancy, such as large tumor size, grade, and more aggressive histological types (carcinosarcoma, micropapillary carcinoma, and malignant adenomyoepithelioma). Similar to these results, HER-2 expression was higher in micropapillary carcinoma and carcinosarcoma. Suggesting the involvement of EGFR and HER-2 in tumor invasion and worse prognosis. Based on these results, it can be assumed that these receptors play different roles in healthy tissues and malignant tumors. Our findings suggest that EGFR and HER-2 receptors appear to play a role in the proliferation of mammary gland tissues in dogs and are associated with the biological aggressiveness of tumors and, therefore, may be potential therapeutic targets also in CMT. Furthermore, we analyzed by LC-MS/MS the protein expression of 26 samples of mammary tissue from dogs (20 TMC and 6 controls). In this study, the most abundant proteins in CMT were identified (Transforming acidic coiled-coil, Proteasome subunit beta, Programmed cell death protein 2, Protein S100A2, Protein S100A9, Rho guanine nucleotide exchange factor 17, Phospholipase A and acyltransferase, A-kinase anchoring protein 6, Galectin and Ketimine reductase mu-crystallin. These proteins with greater abundance in the CMT samples have been shown to be potential biomarkers. Given the apparent similarities between CMT and Human Breast Cancer (HBC), it is possible that such data could also be valuable in the diagnosis and prognosis of HBC.
Canine mammary tumors (CMT) are the most common neoplasms in dogs, with between 35% and 85% of these lesions being malignant. The incidence of these tumors in female dogs is three times higher than in human, although the process is similar. CMT occur most frequently between 8 and 11 years old and, although the exact etiology is unknown, hormonal, nutritional and genetic factors are considered risk factors. The most aggressive types include tubular carcinoma, solid carcinoma, pleomorphic lobular carcinoma, micropapillary carcinoma, and carcinosarcoma. The combination of carcinomas with solid or micropapillary areas can reduce survival time, highlighting the importance of detailed histopathological examination. Mastectomy is the standard treatment except in metastatic cases or inflammatory lesions. The prognosis is based on factors such as clinical evaluation, size of the lesion, metastases detected by imaging tests and histopathological results. The use of specific biomarkers is essential to confirm the diagnosis, evaluate the prognosis and to guide treatment, helping to detect occult metastases and monitor the therapeutic response. In this context, the objective of this work was to identify and quantify the expression of genes and proteins in tumor biopsies and healthy breast tissues, correlating them with clinical and histopathological classifications to evaluate their potential as prognostic factors in the progression of CMT. For the epidemiological study, we analyzed 21 cases of CMT that underwent surgical removal, with these animals being monitored during 24 months. Factors such as breed, age, tumor size, TNM stage, and histopathological results were evaluated. The study found that 77% of the neoplasms analyzed were malignant tumors. Tumor size was correlated with histological grade, and high-level TNM stage was associated with poor overall survival. Multiple tumors were more common in older dogs. Ovariohysterectomy was considered a protective factor for bitches with malignant tumors. Carcinomas in mixed tumors were the most prevalent malignant neoplasms, followed by tubular carcinoma and carcinosarcomas. This study provides information about CMT and emphasizes the importance of knowing factors such as tumor size, histological grade and age of the dog. Timely intervention and follow-up examinations can significantly impact prognosis, and ovariohysterectomy should be considered as a treatment option. In addition, we studied the expression of the EGFR and HER-2 genes in 125 CMT samples. The results show that EGFR mRNA is at higher levels in some CMT tissue subtypes than in healthy tissues. EGFR gene expression levels in tumors were correlated with clinical parameters associated with increased malignancy, such as large tumor size, grade, and more aggressive histological types (carcinosarcoma, micropapillary carcinoma, and malignant adenomyoepithelioma). Similar to these results, HER-2 expression was higher in micropapillary carcinoma and carcinosarcoma. Suggesting the involvement of EGFR and HER-2 in tumor invasion and worse prognosis. Based on these results, it can be assumed that these receptors play different roles in healthy tissues and malignant tumors. Our findings suggest that EGFR and HER-2 receptors appear to play a role in the proliferation of mammary gland tissues in dogs and are associated with the biological aggressiveness of tumors and, therefore, may be potential therapeutic targets also in CMT. Furthermore, we analyzed by LC-MS/MS the protein expression of 26 samples of mammary tissue from dogs (20 TMC and 6 controls). In this study, the most abundant proteins in CMT were identified (Transforming acidic coiled-coil, Proteasome subunit beta, Programmed cell death protein 2, Protein S100A2, Protein S100A9, Rho guanine nucleotide exchange factor 17, Phospholipase A and acyltransferase, A-kinase anchoring protein 6, Galectin and Ketimine reductase mu-crystallin. These proteins with greater abundance in the CMT samples have been shown to be potential biomarkers. Given the apparent similarities between CMT and Human Breast Cancer (HBC), it is possible that such data could also be valuable in the diagnosis and prognosis of HBC.
Descrição
Palavras-chave
tumor de mama em cadelas; biomarcadores; glândula mamária; expressão gênica; proteômica; canine mammary tumor; biomarkers; mammary gland; gene expression; proteomics
Citação
GÖTZE, Marcelo Mendes. Avaliação de biomarcadores associados ao prognóstico de tumores mamários em cadelas. 2024. Tese (Doutorado) – Curso de Biotecnologia, Universidade do Vale do Taquari - Univates, Lajeado, 18 dez. 2024. Disponível em: http://hdl.handle.net/10737/4828.