RESUMEN
Our recent studies showed that cell clusters overlying focal myoepithelial cell layer disruptions (FMCLD) had a significantly higher rate of ER negativity, genetic instabilities, and expression of invasion-related genes than adjacent cells within the same duct. This study attempted to determine if these cells would show aberrant E-cadherin expression, which imparts greater propensity for cell motility and invasion. Consecutive sections from breast tumors with a high frequency of FMCLD were double-immunostained for E-cadherin and a panel of related markers. The E-cadherin mRNA levels in cells overlying FMCLD and adjacent cells within the same duct were compared using real-time PCR. Nearly all the cell clusters overlying FMCLD were strongly immunoreactive for E-cadherin, whereas their adjacent counterparts within the same duct were largely negative. Cell clusters overlying FMCLD were generally arranged as tongue-like projections, "puncturing" deep into the stroma or tube-like structures that often contained red blood cells. The sub-cellular localization of E-cadherin in the above structures, however, was primarily cytoplasmic. The mRNA level of E-cadherin in cell clusters overlying FMCLD was significantly higher than that in adjacent cells within the same duct. These findings suggest that aberrant expression of E-cadherin may contribute to cell motility and invasion.
Asunto(s)
Neoplasias de la Mama/metabolismo , Cadherinas/biosíntesis , Carcinoma Ductal de Mama/metabolismo , Células Epiteliales/metabolismo , Células Musculares/metabolismo , Invasividad Neoplásica/patología , Neoplasias de la Mama/patología , Carcinoma in Situ , Carcinoma Ductal de Mama/patología , Movimiento Celular , Células Epiteliales/patología , Femenino , Expresión Génica , Humanos , Células Musculares/patología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Our recent studies revealed that cell clusters overlying focal myoepithelial cell layer disruption (FMCLD) had a significantly higher frequency of genetic instabilities and expression of invasion-related genes than their adjacent counterparts within the same duct. Our current study attempted to assess whether these cell clusters would also have elevated c-erbB2 expression. Human breast tumors (n=50) with a high frequency of FMCLD were analyzed with double immunohistochemistry, real-time RT-PCR, and chromogenic in situ hybridization for c-erbB2 protein and gene expression. Of 448 FMCLD detected, 404 (90.2%) were associated with cell clusters that had intense c-erbB2 immunoreactivities primarily in their cytoplasm, in contrast to their adjacent counterparts within the same duct, which had no or barely detectable c-erbB2 expression. These c-erbB2 positive cells were arranged as tongue-like projections, "puncturing" into the stroma, and about 20% of them were in direct continuity with tube-like structures that resembled blood vessels. Aberrant c-erbB2 expression was also seen in clusters of architecturally normal-appearing ducts that had distinct cytological abnormalities in both ME and epithelial cells, whereas not in their clear-cut normal counterparts. Molecular assays detected markedly higher c-erbB2 mRNA and gene amplification in cell clusters associated with FMCLD than in those associated with non-disrupted ME cell layers. Our findings suggest that cell clusters overlying FMCLD may represent the precursors of pending invasive lesions, and that aberrant c-erbB2 expression may trigger or signify the emergence of biologically more aggressive cell clones.