Expressão de versican e sua associação com os receptores de superfície celular CD44, EGFR, HER-2 e HER-3 nos tumores produtores de matriz da glândula mamária canina

Abstract

Versican is an extracellular matrix proteoglycan that has been identified as a modulator of cell motility, adhesion loss and tumour progression. This motility results from the interaction between versican and cell surface receptors. Studies have also demonstrated the relationship between this molecule and invasion in canine mammary tumours. Given the evidence for the participation of proteoglycans in tumour progression, this study aimed to assess versican expression and its association with cell surface receptors; human epidermal growth factor receptors 1, 2, and 3 (EGFR, HER-2, and HER-3) and CD44 and gene expressions of EGFR and HER2 in benign mixed tumours (BMTs), carcinomas in mixed tumours (CMTs), and carcinosarcomas (CSs) of the canine mammary gland. Malignant tumours were divided into low and high groups with respect to versican stromal expression. The results indicated that the BMTs showed weak stromal versican expression and correlations between the expression of stromal versican and EGFR in the epithelial membrane in benign areas. A higher stromal versican expression was observed adjacent to invasive epithelial areas compared with in situ areas in CMTs and CSs, suggesting a direct relationship between versican expression and invasiveness. Furthermore, the CSs exhibited a higher expression of HER-2, cytoplasmic HER-3, and CD44 in epithelial invasive cells in cases of higher stromal versican expression. ISH evaluation of EGFR an HER-2 mRNA expression showed a significant difference between in situ and invasive carcinomatous areas in both groups (low and high versican expression), the first showing more dots than the last. No statistical difference was observed between low and high versican expression groups. Therefore, the cell surface receptors (HER-2, HER-3, and CD44) are more evident in CSs that overexpress versican in stroma adjacent to the invasive areas. Furthermore, most EGFR and HER-2 mRNAs as well as proteins expression in in situ carcinomatous areas indicates the involvement of these molecules in early stages of tumour progression. These findings suggest that the association between these molecules may be directly related to the biological behaviour and invasiveness of these canine mammary tumours.