Abstract
The epithelial to mensenchymal transition program regulates various aspects of embryonic development and tissue homeostasis, but aberrant activation of this pathway in cancer contributes to tumor progression and metastasis. TGF-β potently induces an epithelial to mensenchymal transition in cancers of epithelial origin by inducing transcriptional changes mediated by several key transcription factors. Here, we identify the developmental transcription factor SOX4 as a transcriptional target of TGF-β in immortalized human mammary epithelial cells. SOX4 expression and activity are rapidly induced in the early stages of the TGF-β-induced epithelial to mensenchymal transition. We demonstrate that conditional activation of Sox4 is sufficient to induce the expression of N-cadherin and additional mesenchymal markers including vimentin and fibronectin, but fails to induce complete EMT as no changes are observed in the expression of E-cadherin and β-catenin. Moreover, shRNA-mediated knockdown of SOX4 significantly delays TGF-β-induced mRNA and protein expression of mesenchymal markers. Taken together, these data suggest that TGF-β-mediated increased expression of SOX4 is required for the induction of a mesenchymal phenotype during EMT in human mammary epithelial cells.
Highlights
The epithelial to mesenchymal transition (EMT) program is a reversible process important during embryonic development and tissue homeostasis by controlling the formation of the body plan and tissue and organ differentiation [1]
SOX4 is of particular interest since reduced expression through either the endogenous miR-335 or shRNA-mediated knockdown severely impairs the metastatic capacity of MDA-MB-231 cells in mouse xenograft models [11]
Tumor metastasis is the major cause of cancer-related death and in a wide-variety of tumors the epithelial-to-mesenchymal transition has been demonstrated to contribute to this process
Summary
The epithelial to mesenchymal transition (EMT) program is a reversible process important during embryonic development and tissue homeostasis by controlling the formation of the body plan and tissue and organ differentiation [1]. The phenotypic changes observed during TGF-binduced EMT are exerted through alterations in the expression of a variety of transcriptional regulators, including Snail, Slug, Twist, Goosecoid, zinc-finger E-box binding homeobox 1 (ZEB1) and FOXC2 [4]. Most of these transcription factors are transcriptional repressors involved in the direct or indirect down-regulation of Ecadherin expression and a reduction in the epithelial phenotype. Ectopic expression of FOXC2 in epithelial cells is insufficient to induce a full EMT phenotype resulting in increased expression of mesenchymal markers, but lacking complete repression of E-cadherin and other epithelial markers [7]. Conditional activation of SOX4 in non-transformed immortalized HMEC expressing hTERT and SV40 large T and small t antigens (HMLE) was sufficient to drive the expression mesenchymal markers, such as Ncadherin, without affecting expression of the epithelial markers E-
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