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Canine mammary tumors are the most common neoplasms in the bitch. Approximately 50 % of the CMT are histologically diagnosed as malignant. Lymphogenous and haematogenous metastatic spread is common and metastatic disease is the most frequent cause of death in these patients. On the basis of their histological features according to the World Health Organization tumor classification, benign adenomas and malignant carcinomas can easily be distinguished in most cases. Despite worldwide research on mammary cancer, molecular details of the complex metastatic cascade remain unclear. Moreover, the question if the metastatic capacity displays an early inherent feature or a property a tumor acquires in the course of malignant progression remains unanswered. Thus the differentiation between metastasizing and non-metastasizing carcinomas before metastasis is clinically detectable still poses an unresolved challenge.
This study investigated the malignancy associated expression of 16 miRNAs and 4 snoRNAs quantitatively in both non-neoplastic mammary gland and mammary tumors at different stages of malignancy. The mammary tumors were diagnosed histologically and grouped into adenomas, non-metastasizing carcinomas, metastasizing carcinomas and lymph node metastases.
The following main hypothesis was tested: Particular miRNA and snoRNA species are specifically expressed in canine mammary tumors at different stages of malignancy. Thus, their expression pattern allows a differentiation between non-neoplastic mammary gland and neoplastic mammary tissue, benign tumors and malignant tumors as well as between nonmetastasizing and metastasizing carcinomas. Differentially expressed miRNA and snoRNA represent potential biomarkers for cancer diagnosis.
In total nine miRNAs and one snoRNA showed a significantly altered expression in different tissue types. In detail, the expression of five miRNAs (miR-203, miR-143, miR-21, miR-194, miR-210) was increased in at least one primary tumor group versus non-neoplastic mammary gland. Thus, these up-regulated miRNA species might function as oncogenic oncomirs. In contrast, only one snoRNA (U24) was down-regulated in a primary tumor (metastasizing carcinoma) when compared to non-neoplastic mammary gland and therefore might function as a tumor suppressor. In the group of lymph node metastases, three miRNAs (miR-143, miR-145, miR-101) were down-regulated versus non-neoplastic tissue and all primary tumors. One further miRNA (miR-29b) showed a decreased expression in lymph node metastases versus all other groups but non-neoplastic tissue. An increased expression in the group of metastases was only identified for two miRNAs (miR-210, miR-125a). Intriguingly, discrimination of primary tumors at different stages of malignancy was only enabled by miR-125a, which showed a down-regulation in metastasizing carcinomas versus adenomas. Thus, miR-125a allows the differentiation between malignant and benign primary mammary tumors and therefore exhibits the potential for a predictive biomarker in cancer diagnosis. However, the study failed to identify biomarkers for metastatic behavior, which would enable the early differentiation between non-metastasizing and metastasizing carcinomas.
In conclusion, the main hypothesis was supported since the expression of some miRNA and snoRNA was specifically deregulated depending on tumor malignancy. The specific oncogenic or tumor suppressive function of the deregulated RNA species has to be validated in further studies. Although the identification of a biomarker for metastatic behavior failed, this study helps to elucidate the molecular carcinogenesis of canine mammary tumors.