title: WT1 expression in breast cancer disrupts the epithelial/mesenchymal balance of tumour cells and correlates with the metabolic response to docetaxel.
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.
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
authors.forename: Mara
authors.initials: M
authors.lastname: Artibani
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sims
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
authors.forename: Joan
authors.initials: J
authors.lastname: Slight
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Aitken
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Thornburn
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
authors.forename: Morwenna
authors.initials: M
authors.lastname: Muir
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Brunton
authors.affiliation: Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Midlothian, EH25 9RG, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Del-Pozo
authors.affiliation: Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Midlothian, EH25 9RG, UK.
authors.forename: Linda R
authors.initials: LR
authors.lastname: Morrison
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
authors.forename: Elad
authors.initials: E
authors.lastname: Katz
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.|The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian, EH25 9RG, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Hohenstein
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D000077143:Docetaxel; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D061986:MCF-7 Cells; D009154:Mutation; D011379:Prognosis; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D025721:WT1 Proteins; C583751:WT1 protein, human; D000077143:Docetaxel; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human