Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands.
Breast Cancer Res Treat. 2012 May;133(1):49-59. doi: 10.1007/s10549-011-1684-y. Epub 2011 Jul 28.
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.
上皮间质转化（EMT）在转移的发展中起着重要作用。EMT 的一个标志是 E-钙黏蛋白的丢失和 N-钙黏蛋白表达的获得，这是由转录因子如 SNAIL、SLUG 和 TWIST 调节的。我们在一组经过描述的接受过原发手术治疗的大型乳腺癌患者队列中，研究了这些因素以及 E-钙黏蛋白和 N-钙黏蛋白的预后价值。由于这些转录因子的表达受到雌激素受体（ER）状态的调控，因此我们对这些分析进行了分层。使用免疫组织化学在包含 575 例乳腺癌肿瘤的 TMA 上检测 SNAIL、SLUG 和 TWIST 的表达。使用加权组织评分（histoscore）对核表达进行定量，并根据中位数组织评分将其分为高表达和低表达。在分别有 54%、50%和 50%的肿瘤中，SNAIL、SLUG 和 TWIST 的表达水平较高。SNAIL（P = 0.014）和 TWIST（P = 0.006）的表达水平与患者无复发生存期较差相关，特别是在 ER 阳性肿瘤患者中（交互 Cox 比例风险 P = 0.039）。将这两个因素结合起来，可以形成具有高判别能力的独立预后因素（两者均低比两者均高：HR 1.15；两者均低比两者均高 HR 1.84；P = 0.010）。SNAIL-TWIST 的共表达与低 E-钙黏蛋白和高 N-钙黏蛋白表达相关，特别是在 ER 阳性肿瘤中（P = 0.009），这表明 SNAIL 和 TWIST 通过与 ER 的相互作用可能调节 E-和 N-钙黏蛋白的表达，从而诱导 EMT。我们的结果表明，SNAIL 和 TWIST 通过调节 E-和 N-钙黏蛋白的表达，在 EMT 中发挥关键作用，这仅在 ER 阳性乳腺癌患者中发生。
