Article

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

Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands.
Breast Cancer Research and Treatment (Impact Factor: 4.2). 07/2011; 133(1):49-59. DOI: 10.1007/s10549-011-1684-y
Source: PubMed

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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    • "Briefly, the proportion of cells with nuclear staining was multiplied by the intensity of staining to provide a histoscore ranging from 0–300. The histoscore was calculated as follows: Score = (0 × percentage not stained) + (1 × percentage weakly stained) + (2 × percentage moderately stained) + (3 × percentage strongly stained) [14]. "
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    ABSTRACT: Background Matrix metalloproteinases (MMPs) are involved in cancer invasion and metastasis. Circulating tumor cells (CTCs) play role in tumor dissemination and are an independent survival predictor in breast cancer (BC) patients. The aim of this study was to assess correlation between CTCs and tumor MMP1 in BC. Methods Study included 149 primary BC patients treated by surgery from March 2012 to March 2013. Peripheral blood mononuclear cells (PBMC) were depleted of hematopoietic cells using RossetteSepTM selection kit. RNA extracted from CD45-depleted PBMC was interrogated for expression of EMT (TWIST1, SNAIL1, SLUG, ZEB1) and epithelial (CK19) gene transcripts by qRT-PCR. Patient samples with higher epithelial and/or mesenchymal gene transcripts than those of healthy donors (n = 60) were considered as CTC positive. Expression of MMP1 in surgical specimens was evaluated by immunohistochemistry. Results CTCs were detected in 24.2% patients. CTCs exhibiting only epithelial markers were present in 8.7% patients, whereas CTCs with epithelial-mesenchymal transition (EMT) markers (CTC_EMT) were observed in 13.4% of patients and CTCs co-expressing both markers were detected in 2.0% patients. Patients with CTC_EMT in peripheral blood had significantly increased expression of MMP1 in tumor cells (p = 0.02) and tumor associated stroma (p = 0.05) than those of patients without CTC_EMT. In multivariate analysis, CTC_EMT and tumor grade were independently associated with MMP1 expression in cancer cells, while CTC_EMT and Ki67 were independently associated with MMP1 expression in cancer associated stroma. Conclusion Our data suggest link between MMP1 and CTCs with EMT phenotype and support role of MMPs and EMT in tumor dissemination.
    BMC Cancer 06/2014; 14(1):472. DOI:10.1186/1471-2407-14-472 · 3.32 Impact Factor
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    • "Previous studies have demonstrated that SRC-1 is significantly increased in 34% 21 and Twist1 is significantly increased in 50% 22 of breast tumors, In the current study, we found that 44.5% cases were SRC-1 positive and 46.7% cases were Twist1 positive. Our results are consistent with previous reports. "
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    ABSTRACT: To evaluate the possible prognostic value of Steroid Receptor Coactivator-1 (SRC-1) and Twist1 expression in human breast cancer, we examined SRC-1 and Twist1 expression using immunohistochemistry on tissue microarray sections containing 137 breast cancer specimens. All patients were followed up for a median of 5 years following surgery. Survival curves were generated using the Kaplan-Meier method. Multivariate analysis was performed using the Cox proportional hazard regression model to assess the prognostic values. The results showed a positive correlation between SRC-1 and Twist1 expression at protein levels (P < 0.001). Also, SRC-1 expression positively correlated with HER2 expression (P = 0.024). The protein expression of Twist1 positively associated with lymph node metastasis (P < 0.001), but inversely correlated with PR status (P = 0.041). Patients with SRC-1 or Twist1-positive expression exhibited poorer overall survival (OS) and disease-free survival (DFS) than did those with SRC-1 or Twist1-negative expression (P < 0.05 for all). In addition, SRC-1-negativeive/Twist1-negative patients had the best OS and DFS (P < 0.01 for both). In multivariate survival analysis, SRC-1 expression, tumor stage, and PR were found to be independent prognostic factors related to OS (P = 0.019, < 0.001 and 0.02, respectively) and Twist1 expression, lymph node status and PR were independent predictors of DFS (P = 0.006, 0.001 and 0.029, respectively). These results suggest that a combined SRC-1/Twist1 expression status could improve the prognostic judgment for breast cancer patients.
    International journal of biological sciences 03/2014; 10(4):396-403. DOI:10.7150/ijbs.8193 · 4.37 Impact Factor
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    • "Studies have also shown that Snail plays an essential role in the progression and metastatic process of human pancreatic cancer[9], [10]. In clinical setting, Snail overexpression has previously been associated with poorer prognosis and a more invasive phenotype in many malignancies[11]–[13]. However, few reports exist regarding the link between Snail expression and the gain of pancreatic cancer stem cell properties. "
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    PLoS ONE 01/2014; 9(1):e87409. DOI:10.1371/journal.pone.0087409 · 3.23 Impact Factor
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