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Loss of Dickkopf 3 Promotes the Tumorigenesis of Basal Breast Cancer
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 subty...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965070/ https://www.ncbi.nlm.nih.gov/pubmed/27467270 http://dx.doi.org/10.1371/journal.pone.0160077 |
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author | Lorsy, Eva Topuz, Aylin Sophie Geisler, Cordelia Stahl, Sarah Garczyk, Stefan von Stillfried, Saskia Hoss, Mareike Gluz, Oleg Hartmann, Arndt Knüchel, Ruth Dahl, Edgar |
author_facet | Lorsy, Eva Topuz, Aylin Sophie Geisler, Cordelia Stahl, Sarah Garczyk, Stefan von Stillfried, Saskia Hoss, Mareike Gluz, Oleg Hartmann, Arndt Knüchel, Ruth Dahl, Edgar |
author_sort | Lorsy, Eva |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4965070 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-49650702016-08-18 Loss of Dickkopf 3 Promotes the Tumorigenesis of Basal Breast Cancer Lorsy, Eva Topuz, Aylin Sophie Geisler, Cordelia Stahl, Sarah Garczyk, Stefan von Stillfried, Saskia Hoss, Mareike Gluz, Oleg Hartmann, Arndt Knüchel, Ruth Dahl, Edgar PLoS One Research Article 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. Public Library of Science 2016-07-28 /pmc/articles/PMC4965070/ /pubmed/27467270 http://dx.doi.org/10.1371/journal.pone.0160077 Text en © 2016 Lorsy et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Lorsy, Eva Topuz, Aylin Sophie Geisler, Cordelia Stahl, Sarah Garczyk, Stefan von Stillfried, Saskia Hoss, Mareike Gluz, Oleg Hartmann, Arndt Knüchel, Ruth Dahl, Edgar Loss of Dickkopf 3 Promotes the Tumorigenesis of Basal Breast Cancer |
title | Loss of Dickkopf 3 Promotes the Tumorigenesis of Basal Breast Cancer |
title_full | Loss of Dickkopf 3 Promotes the Tumorigenesis of Basal Breast Cancer |
title_fullStr | Loss of Dickkopf 3 Promotes the Tumorigenesis of Basal Breast Cancer |
title_full_unstemmed | Loss of Dickkopf 3 Promotes the Tumorigenesis of Basal Breast Cancer |
title_short | Loss of Dickkopf 3 Promotes the Tumorigenesis of Basal Breast Cancer |
title_sort | loss of dickkopf 3 promotes the tumorigenesis of basal breast cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965070/ https://www.ncbi.nlm.nih.gov/pubmed/27467270 http://dx.doi.org/10.1371/journal.pone.0160077 |
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