Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma

Authors

  • Sivan Elloul M.Sc.,

    1. Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
    Search for more papers by this author
  • Mari Bukholt Elstrand M.D.,

    1. Department of Gynecologic Oncology, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway
    Search for more papers by this author
  • Jahn M. Nesland M.D., Ph.D.,

    1. Department of Pathology, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway
    Search for more papers by this author
  • Claes G. Tropé M.D., Ph.D.,

    1. Department of Gynecologic Oncology, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway
    Search for more papers by this author
  • Gunnar Kvalheim M.D., Ph.D.,

    1. Department of Oncology, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway
    Search for more papers by this author
  • Iris Goldberg Ph.D.,

    1. Department of Pathology, Sheba Medical Center, affiliated with the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
    Search for more papers by this author
  • Reuven Reich Ph.D.,

    1. Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
    Search for more papers by this author
    • Reuven Reich, Ph.D. is affiliated with the David R. Bloom Center for Pharmacy at the Hebrew University.

  • Ben Davidson M.D., Ph.D.

    Corresponding author
    1. Department of Pathology, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway
    • Department of Pathology, The Norwegian Radium Hospital, Montebello N-0310 Oslo, Norway
    Search for more papers by this author
    • Fax: (011) 47 22508554


  • The authors dedicate this study to the memory of Dr. Iris Goldberg, a close friend and a collaborator for many years.

  • Presented at the 10th International Congress of the Metastasis Research Society, Genoa, Italy, September 17–20, 2004.

Abstract

BACKGROUND

It was demonstrated previously that the Snail family of transcription factors and Smad-interacting protein 1 (Sip1) regulate E-cadherin and matrix metalloproteinase 2 (MMP-2) expression, cellular morphology, and invasion in carcinoma. For the current study, the authors analyzed the relation between the expression of Snail, Slug, and Sip1; the expression of MMP-2 and E-cadherin; and clinical parameters in patients with metastatic ovarian and breast carcinoma.

METHODS

One hundred one fresh-frozen, malignant effusions from patients who were diagnosed with gynecologic carcinomas (78 ovarian carcinomas and 23 breast carcinomas) were studied for mRNA expression of Snail, Slug, Sip1, MMP-2, and E-cadherin using reverse transcriptase-polymerase chain reaction analysis. Snail mRNA and E-cadherin protein expression levels also were studied in ovarian carcinoma effusions using in situ hybridization and immunocytochemistry. The results were analyzed for possible correlation with clinicopathologic parameters in both tumor types.

RESULTS

E-cadherin mRNA expression was lower in breast carcinoma (P = 0.001), whereas Snail expression was higher (P = 0.003). The Snail/E-cadherin ratio (P < 0.001) and the Sip1/E-cadherin ratio (P = 0.002) were higher in breast carcinomas. Sip1 mRNA expression (P < 0.001) and Slug mRNA expression (P < 0.001) were correlated with the expression of MMP-2 in ovarian carcinomas. The Sip1/E-cadherin ratio was higher in primary ovarian carcinomas at the time of diagnosis compared with postchemotherapy ovarian carcinoma effusions (P = 0.003), higher in Stage IV tumors compared with Stage III tumors (P = 0.049), and higher in pleural effusions compared with peritoneal effusions (P = 0.044). In a univariate survival analysis of patients with ovarian carcinoma, a high Sip1/E-cadherin ratio predicted poor overall survival (P = 0.018). High E-cadherin mRNA expression predicted better disease-free survival (P = 0.023), with a similar trend for a low Slug/E-cadherin ratio (P = 0.07). High Snail mRNA expression predicted shorter effusion-free survival (P = 0.008), disease-free survival (P = 0.03), and overall survival (P = 0.008) in patients with breast carcinoma.

CONCLUSIONS

Transcription factors that regulate E-cadherin were expressed differentially in metastatic ovarian and breast carcinoma. Snail may predict a poor outcome in patients who have breast carcinoma metastatic to effusions. E-cadherin expression generally was conserved in effusions from patients with ovarian carcinoma, but the subset of patients with postulated Sip1-induced repression of this adhesion molecule had a significantly worse outcome. This finding was in agreement with the stronger suppression of E-cadherin by Snail and Sip1 in breast carcinoma effusions, a clinical condition associated with extremely poor survival. Cancer 2005. © 2005 American Cancer Society.

Ancillary