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Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor–positive early breast cancer patients

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Abstract

Epithelial mesenchymal transition (EMT) plays an important role in the development of metastases. One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by transcription factors, such as SNAIL, SLUG, and TWIST. We examined the prognostic value of these factors as well as E-cadherin and N-cadherin, in a well-described large cohort of breast cancer patients treated with primary surgery. Analyses were stratified by estrogen receptor (ER) status, because of its crucial role in the regulation of these transcription factors. SNAIL, SLUG, and TWIST expression were examined on a TMA containing 575 breast tumors using immunohistochemistry. Nuclear expression was quantified using a weighted histoscore and classified as high versus low expression, based on the median histoscore. High expression of SNAIL, SLUG, and TWIST was seen in 54, 50, and 50% of tumors, respectively. The level of SNAIL (P = 0.014) and TWIST (P = 0.006) expression was associated with a worse patient relapse-free period, specifically in patients with ER-positive tumors (interaction Cox proportional hazards P = 0.039). Combining both factors resulted in an independent prognostic factor with high discriminative power (both low versus either high: HR 1.15; both low versus both high HR 1.84; P = 0.010). Co-expression of SNAIL–TWIST was associated with low-E-cadherin and high-N-cadherin expression, especially in ER-positive tumors (P = 0.009), suggesting that, through interactions with ER, SNAIL and TWIST may regulate E- and N-cadherin expression, thereby inducing EMT. Our results are indicative that SNAIL and TWIST play a crucial role in EMT through regulation of E- and N-cadherin expression, exclusively in ER-positive breast cancer patients.

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Acknowledgments

We thank Professor Ismo Virtanen for using his SNAIL antibody. We regret that he passed away during the publication process. We thank Johanna Pedraza and InHwa Um and other colleagues of the Endocrine Cancer Group for their help in the laboratory. We thank Jan Molenaar for his help with the database. This research has been supported by grants of a Dutch Surgical Foundation “Stichting Prof. Michaël-van Vloten Fonds,” by the Foundation “De Drie Lichten” in the Netherlands, by an unrestricted educational research grant of Pfizer UK, and by the Dutch Cancer Society (KWF 2007-3968).

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Authors and Affiliations

  1. Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands

    Johanna G. H. van Nes, Esther M. de Kruijf, Gerrit-Jan Liefers, Peter J. K. Kuppen & Cornelis J. H. van de Velde

  2. Department of Radiation Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands

    Johanna G. H. van Nes

  3. Department of Medical Statistics, Leiden University Medical Centre, Leiden, The Netherlands

    Hein Putter

  4. Department of Pathology, Endocrine Cancer Group, Edinburgh Cancer Research Centre, Western General Hospital, Crewe Road South, EH4 2XR, Edinburgh, UK

    Dana Faratian, Alison Munro, Fiona Campbell & John M. S. Bartlett

  5. Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands

    Vincent T. H. B. M. Smit

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  1. Johanna G. H. van Nes
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  2. Esther M. de Kruijf
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  3. Hein Putter
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  7. Vincent T. H. B. M. Smit
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  9. Peter J. K. Kuppen
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  10. Cornelis J. H. van de Velde
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  11. John M. S. Bartlett
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Corresponding author

Correspondence to John M. S. Bartlett.

Additional information

The authors Johanna G.H. van Nes, and Esther M. de Kruijf contributed equally to the study and the manuscript.

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van Nes, J.G.H., de Kruijf, E.M., Putter, H. et al. Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor–positive early breast cancer patients. Breast Cancer Res Treat 133, 49–59 (2012). https://doi.org/10.1007/s10549-011-1684-y

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  • DOI: https://doi.org/10.1007/s10549-011-1684-y

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