Abstract 2303: The redox-active protein thioredoxin: A modulator of epithelial-mesenchymal transition

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Human thioredoxin is a ubiquitous redox-active protein that induces the activation of many redox-sensitive transcription factors, inhibits the activity of the apoptosis-signal regulating kinase, and activates the AKT signaling pathway. Thioredoxin is thus associated with many biological processes, including the induction of cellular proliferation leading to cancer progression and metastasis. The morphogenetic changes occurring during the initial stage of metastasis is referred to as epithelial-mesenchymal transition (EMT). EMT results in the transition of cancer cells from an epithelial to a fibroblastic or mesenchymal phenotype, accompanied by a large number of changes in gene expression, particularly down regulation in the expression of the epithelial marker E-cadherin and induction of expression and activation of the mesenchymal marker vimentin, N-cadherin, or fibronectin. Transforming growth factor (TGF)-β is regarded as the prototype cytokine for induction of EMT both in vitro and in vivo. Using a high throughput functional genomic screen, we previously showed that members of the TGF-β signaling pathway induce the expression of thioredoxin in both pancreatic and breast cancer cells. In addition, we showed that TGF-β1 stimulation in these cells resulted in a two-fold induction of thioredoxin expression. Therefore, we hypothesized that thioredoxin is a modulator of EMT. We based this hypothesis on the finding that increased expression of thioredoxin is associated with metastasis and that TGF-β1 induces thioredoxin expression. Herein we present evidence in both breast cancer cells and human biopsy samples of breast tumors that support our hypothesis. In vitro three-dimensional cell cultures of the MDA-MB-231 breast cancer cell line undergo phenotypic changes similar to the morphogenetic changes associated with EMT. Treating MDA-MB-231 cells with PX12, a potent inhibitor of thioredoxin, blocked the onset of these morphogenetic changes. We show a correlation between the expression of thioredoxin and the EMT markers utilizing Reverse-Phase Protein Array of 250 fine-needle aspirates from breast tumor patients and the Pearson correlation coefficients. There was a positive correlation between thioredoxin and N-cadherin (p<0.0001), and a negative correlation between thioredoxin and E-cadherin (p<0.0001) as well as between thioredoxin and β-catenin (p<0.0001). High expression of thioredoxin correlate with decreased expression of E-cadherin and β-catenin and an increased expression of N-cadherin. Our data demonstrated that thioredoxin might be an important regulator of EMT in breast cancer. Based on our findings we propose a model indicating that thioredoxin modulates TGF-β-induced EMT by functioning to maintain EMT once it is initiated. Ongoing studies by our group will enable us to confirm this model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2303.