Abstract
Carcinoma progression is linked to a partially dedifferentiated epithelial cell phenotype. As previously suggested, this regulation could involve transcription factors, Snail and Slug, known to promote epithelial-mesenchymal transitions during development. Here, we investigate the role of Snail and Slug in human breast cancer progression. We analyzed Snail, Slug, and E-cadherin RNA expression levels and protein localization in large numbers of transformed cell lines and breast carcinomas, examined the correlation with tumor histologic features, and described, at the cellular level, Snail and Slug localization in carcinomas using combined in situ hybridization and immunolocalization. In contrast with transformed cell lines, Slug was found to colocalize with E-cadherin at the cellular level in normal mammary epithelial cells and all tested carcinomas. Snail also colocalized at the cellular level with E-cadherin in tumors expressing high levels of Snail RNA. In addition, Snail was significantly expressed in tumor stroma, varying with tumors. Slug and Snail genes were significantly overexpressed in tumors associated with lymph node metastasis. Finally, the presence of semidifferentiated tubules within ductal carcinomas was linked to Slug expression levels similar to or above normal breast samples. These results suggest that Snail or Slug expression in carcinoma cells does not generally preclude significant E-cadherin expression. They emphasize a link between Snail, Slug, and lymph node metastasis in a large sampling of mammary carcinomas, and suggest a role for Slug in the maintenance of semidifferentiated structures. Snail and Slug proteins seem to support distinct tumor invasion modes and could provide new therapeutic targets.
Highlights
Carcinoma progression is linked to a partially dedifferentiated epithelial cell phenotype
Slug was linked to the clinical progression of lung carcinoma [16] three studies in distinct mouse models have recently shown the direct involvement of Snail [17, 18] and Slug [17] in tumor progression
Slug and Snail are negatively correlated with E-cadherin expression in breast cancer cell lines, but not in human mammary epithelial cells (HMEC)
Summary
Carcinoma progression is linked to a partially dedifferentiated epithelial cell phenotype. The roles of Snail and Slug in cancer progression have been postulated by several groups, based on distinct lines of evidence involving RNA studies, cell models, and clinical correlations (12 – 14). Slug was linked to the clinical progression of lung carcinoma [16] three studies in distinct mouse models have recently shown the direct involvement of Snail [17, 18] and Slug [17] in tumor progression. Considering the converging data suggesting a role for Snail genes during breast carcinoma progression, we initiated an exhaustive screening of normal and transformed cells to detect links between Slug, Snail, E-cadherin and tumor progression status. A new and intriguing expression pattern of Snail and Slug emerged from these studies and suggests distinct functions for the two transcription factors
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