Abstract
WT1 is a transcription factor which regulates the epithelial-mesenchymal balance during embryonic development and, if mutated, can lead to the formation of Wilms’ tumour, the most common paediatric kidney cancer. Its expression has also been reported in several adult tumour types, including breast cancer, and usually correlates with poor outcome. However, published data is inconsistent and the role of WT1 in this malignancy remains unclear. Here we provide a complete study of WT1 expression across different breast cancer subtypes as well as isoform specific expression analysis. Using in vitro cell lines, clinical samples and publicly available gene expression datasets, we demonstrate that WT1 plays a role in regulating the epithelial-mesenchymal balance of breast cancer cells and that WT1-expressing tumours are mainly associated with a mesenchymal phenotype. WT1 gene expression also correlates with CYP3A4 levels and is associated with poorer response to taxane treatment. Our work is the first to demonstrate that the known association between WT1 expression in breast cancer and poor prognosis is potentially due to cancer-related epithelial-to-mesenchymal transition (EMT) and poor chemotherapy response.
Highlights
The Wilms’ Tumour gene 1 (WT1), encodes for a complex protein with transcription factor activity which is essential in mammals throughout life[1]
We have studied the relationship between WT1 expression and the overall epithelial/mesenchymal balance of breast cancer using in vitro cell lines, clinical samples and publicly available gene expression datasets in order to better investigate why WT1 is usually associated with poor prognosis
The role of WT1 in breast cancer and its significance in terms of prognosis remain unclear, with conflicting results being reported in the literature
Summary
The Wilms’ Tumour gene 1 (WT1), encodes for a complex protein with transcription factor activity which is essential in mammals throughout life[1]. Besides being recently linked to chemoresistance[32,33], cancer-related EMT has long been associated with the acquisition of a malignant phenotype by the epithelial tumour cells: features of EMT have been described in breast[34] and colorectal cancer[35], mainly at the invasive front of the tumour This suggests that the EMT may generate migratory cells which leave the primary site, invade the blood vessels and potentially metastasise. This theory on EMT contribution to tumour progression is supported by the fact that many developmental EMT drivers, including SNAIL, SLUG, TWIST and ZEB1, are aberrantly expressed in cancer and significantly correlate with relapse and poor clinical outcomes[36,37,38]. WT1 has been shown to regulate the EMT which occurs in the developing epicardium[2] as well as the MET which is required for nephrogenesis[3] and its transcriptional targets include SNAIL, SLUG and TGF-β2,39,40
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