Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor–positive early breast cancer patients
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.
KeywordsEarly breast cancer Prognostic factors SNAIL SLUG TWIST
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).
Conflict of interests
- 23.van Nes JGH, de Kruijf EM, Faratian D, van de Velde CJ, Putter H, Falconer C, Smit VT, Kay C, van de Vijver MJ, Kuppen PJ, Bartlett JM (2011) COX2 expression in prognosis and in prediction to endocrine therapy in early breast cancer patients. Breast Cancer Res Treat 125:671–685PubMedCrossRefGoogle Scholar
- 26.Altman DG, Machin D, Bryant TN, Gardner MJ (2000) Statistics with confidence. British Medical Journal Books, BristolGoogle Scholar