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Expression of the Epithelial Mesenchymal Transition Regulator Snail in Metaplastic Breast Carcinomas with Chondroid Differentiation K Gwin, A Contreras, M Tretiakova, A Montag The University of Chicago Medical Center, Chicago, IL Score The epithelial mesenchymal transition (EMT) is an essential process during normal embryogenesis in which polarized, immotile epithelia acquire a highly motile, fibroblastoid phenotype. EMT is characterized by the loss of cell-cell adhesion, apical-basal cell polarity and increased motility of cells. In epithelial tumors, EMT is an important process during tumor progression and development of metastasis. Tumor cells gain the ability to invade tissues and to migrate to distant regions. EMT is regulated by transcription factors such as Snail that downregulate epithelial and upregulate mesenchymal genes. The transcription factor Snail is considered one of the key regulators of EMT as it particularly functions in repression of transcription of E-Cadherin. Metaplastic breast carcinomas with chondroid differentiation (MBC) show a combined epithelial and mesenchymal chondromyxoid matrix with features reminiscent of EMT. MBC may therefore be a potential in vivo model for EMT, and increased expression of Snail in both tumor components might be present. Archival paraffin embedded material of 12 MPC, as defined by the 2003 WHO classification, and 1 lymph node metastasis were retrieved from the files of the Pathology Department. The lymph node metastases showed only the epithelial component. Selected 4 m thick formalin-fixed deparaffinized sections were stained with primary anti-human Rabbit Polyclonal antibody SNAI1 (Aviva Systems Bio). Cytoplasmic and nuclear expression in the areas of strongest positivity was determined in 50-100 tumor cells separately for both tumor components. In accordance with previous studies nuclear snail expression was evaluated as follows: 0, immunoreactivity of < 1% of tumor cells; 1+, immunoreactivity of 1% of tumor cells; 2+ immunoreactivity of 2-5% of tumor cells; 3+, immunoreactivity of >5% of tumor cells. A D B Figure 2. (A) Axillary lymph node metastases with positive nuclear and cytoplasmic Snail expression (B) Normal breast parenchyma reveals no expression of Snail. Location Infiltrating ductal component LN metastases 0, Negative 1 0 - 1+, Positive 0 1 - 2+, Positive 10 1 - 3+, Positive 1 10 1 The one axillary lymph node metastasis available for review, composed only of the epithelial component of the primary breast carcinoma, showed nuclear Snail expression in 12% of tumor cells. Of interest, the corresponding primary breast tumor exhibited nuclear Snail expression in only in 4% of tumor cells of the infiltrating ductal carcinoma, but in 70% of the metaplastic carcinoma component. Snail was not expressed in adjacent normal mammary tissue. Figure 1. : MBC (A) On low magnification, a significant difference of Snail expression in both tumor components is found (B) The interphase of ductal carcinoma and metaplastic chondroid matrix shows an increase in nuclear expression (C) Infiltrating ductal component with mostly cytoplasmic staining. (D) Metaplastic chondroid component with predominantly nuclear staining. A Metaplastic chondroid component Table 2: Nuclear Snail expression in breast carcinoma with chondroid differentiation (n=12) B C Infiltrating duct component Chondroid component LN metastases Nuclear 4.00% 33.70% 12% 94.80% 66.30% 88% Cytoplasmic Table 1: A total of 91.6% of MBC revealed simultaneous nuclear and cytoplasmic staining in both the regular infiltrating ductal and in the metaplastic chondroid component. The tumor cells with metaplastic features revealed a significantly higher frequency of nuclear Snail expression (33.7) than those of regular ductal carcinoma (4.0%) (p< 0.005) Gene expression studies have demonstrated a distinctive gene expression profile for MBC that is supportive of our findings showing that several of the overexpressed genes, including Snail, were functionally related to adhesion, motility, migration and extracellular matrix formation. Of interest is the location and distribution between cytoplasmic and nuclear expression of Snail in the two tumor components in our study. In addition to being tightly regulated at the transcriptional level, the activity of Snail is also influenced by its subcellular localization. Snail can cycle between nucleus and cytosol. Two kinases, GSK-3 and PAK-1 are known regulate the function of Snail. There is now mounting evidence that Snail protein expression in the cytoplasm represents an inactive form of the protein. Our study found expression of nuclear-localized, active Snail protein predominantly in the chondroid matrix and to a lesser amount in the ductal component. Nuclear expression was especially high at the interphase of both components. These finding suggest that the metaplastic Snail positive cells underwent EMT and acquired a mesenchymal phenotype. Another notable finding was the increase in active Snail protein in the LN metastasis. As Snail has also a recognized function in blocking the cell cycle and conferring resistance to cell death, preserved Snail expression might be a capacity for survival of metastasis.