title: Loss of Dickkopf 3 Promotes the Tumorigenesis of Basal Breast Cancer.
abstract: Dickkopf 3 (DKK3) has been associated with tumor suppression of various tumor entities including breast cancer. However, the functional impact of DKK3 on the tumorigenesis of distinct molecular breast cancer subtypes has not been considered so far. Therefore, we initiated a study analyzing the subtype-specific DKK3 expression pattern as well as its prognostic and functional impact with respect to breast cancer subtypes. Based on three independent tissue cohorts including one in silico dataset (n = 30, n = 463 and n = 791) we observed a clear down-regulation of DKK3 expression in breast cancer samples compared to healthy breast tissue controls on mRNA and protein level. Interestingly, most abundant reduction of DKK3 expression was detected in the highly aggressive basal breast cancer subtype. Analyzing a large in silico dataset comprising 3,554 cases showed that low DKK3 mRNA expression was significantly associated with reduced recurrence free survival (RFS) of luminal and basal-like breast cancer cases. Functionally, DKK3 re-expression in human breast cancer cell lines led to suppression of cell growth possibly mediated by up-regulation of apoptosis in basal-like but not in luminal-like breast cancer cell lines. Moreover, ectopic DKK3 expression in mesenchymal basal breast cancer cells resulted in partial restoration of epithelial cell morphology which was molecularly supported by higher expression of epithelial markers like E-Cadherin and down-regulation of mesenchymal markers such as Snail 1. Hence, we provide evidence that down-regulation of DKK3 especially promotes tumorigenesis of the aggressive basal breast cancer subtype. Further studies decoding the underlying molecular mechanisms of DKK3-mediated effects may help to identify novel targeted therapies for this clinically highly relevant breast cancer subtype.
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Lorsy
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Aylin Sophie
authors.initials: AS
authors.lastname: Topuz
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Cordelia
authors.initials: C
authors.lastname: Geisler
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Stahl
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Garczyk
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: von Stillfried
authors.affiliation: Electron Microscopy Facility, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Hoss
authors.affiliation: West German Study Group, Breast Center Niederrhein, Bethesda Hospital, Monchengladbach, Germany.
authors.forename: Oleg
authors.initials: O
authors.lastname: Gluz
authors.affiliation: Institute of Pathology, University Hospital Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Knüchel
authors.affiliation: Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Dahl
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D018925:Chemokines; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D061986:MCF-7 Cells; D016612:Paraffin Embedding
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins