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Snail and Slug Play Distinct Roles during Breast Carcinoma Progression

Authors' Affiliations: ¹ EMI229 Institut National de la Sante et de la Recherche Medicale, Genotypes et Phenotypes Tumoraux, Centre de Recherche en Cancerologie, CRLC Val d'Aurelle-Paul Lamarque, ² Institut de Génétique Humaine, UPR 1142 Centre National de la Recherche Scientifique, Montpellier, France, and ³ Klinikum Rechts der Isar der Technischen Universitaet, Institut fuer Pathologie, Munich, Germany

Requests for reprints: Pierre Savagner, EMI229 Institut National de la Sante et de la Recherche Medicale, Génotypes et Phénotypes Tumoraux, Batiment de Recherche en Cancerologie, CRLC Val d'Aurelle-Paul Lamarque, 34298 Montpellier cedex 5, France. Phone: 33-46761-8523/8524; Fax: 33-46761-3041; E-mail: psavagner{at}valdorel.fnclcc.fr.

Purpose: 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.

Experimental Design: 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.

Results: 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.

Conclusions: 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.

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