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Dissecting the roles of WNT signaling in breast cancer using "in vitro" and "in vivo" experimental models

Matsuda, Yutaka. Dissecting the roles of WNT signaling in breast cancer using "in vitro" and "in vivo" experimental models. 2009, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_8605

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Abstract

Canonical WNT pathway regulates expression of target genes by modulating intracellular amount of β-catenin. Without WNT pathway activation, a so-called “destruction complex” including APC and Axin facilitates the degradation of β-catenin. Upon binding of WNT ligand to its receptor Frizzled, the destruction complex is antagonized and β-catenin is stabilized. Stabilized β-catenin goes to the nucleus, binds to the TCF/LEF family of transcription factors and initiates the new gene expression program.
De-regulation of the WNT signaling pathway via mutations in APC and Axin, proteins that target β-catenin for destruction, or in β-catenin itself have been linked to various types of human cancer. These genetic alterations rarely, if ever, are observed in breast tumors. However, various lines of evidence suggest that WNT signaling may also be de-regulated in breast cancer. Most breast tumors show hypermethylation of the promoter region of secreted Frizzled-related protein 1 (sFRP1), a WNT antagonist, leading to downregulation of its expression. As a consequence WNT signaling is enhanced. We hypothesized that autocrine activation of WNT signaling plays an important role in breast cancer and loss of sFRP1 expression is one of the critical events leading to constitutively active WNT signaling in breast cancer formation.
We show that de-regulation of the WNT signaling pathway appears to occur by autocrine mechanisms in a panel of breast cancer cell lines and that interference with WNT signaling in breast cancer cell lines reduces their proliferative ability. Furthermore, ectopic expression of sFRP1 suppresses autocrine WNT signaling in MDA-MB-231 human breast cancer cells and leads to dramatically impaired outgrowth of these cells as xenografts in nude mice. A microarray analysis led to the identification of two genes encoding CCND1 and CDKN1A whose
expression level is selectively altered in sFRP1 expressing tumors. The corresponding proteins, cyclin D1 and p21Cip1 were down- and up-regulated, respectively in sFRP1 expressing tumors, suggesting that they are downstream mediators of WNT signaling. In addition to the effect on cell proliferation, we show that WNT stimulates the migratory ability of T47D human breast cancer cells. Conversely, ectopic expression of sFRP1 decreases the migratory potential of MDA-MB231 cells, suggesting that WNT activation not only promotes cell growth, but also stimulates cell motility.
In summary, these results suggest that the WNT pathway has an impact on various biological characteristics of human breast cancer cell lines. Throughout these studies, we revealed the possibility that interference with WNT signaling at the ligand-receptor level is a valid therapeutic approach in breast cancer.
Advisors:Hynes, Nancy
Committee Members:Christofori, Gerhard M.
Faculties and Departments:09 Associated Institutions > Friedrich Miescher Institut FMI
Item Type:Thesis
Thesis no:8605
Bibsysno:Link to catalogue
Number of Pages:135
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:41
Deposited On:08 Apr 2009 18:32

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