The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer

Loh, Yan Ni, Hedditch, Ellen L., Baker, Laura A., Jary, Eve, Ward, Robyn L. and Ford, Caroline E. (2013) The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer. BMC Cancer, 13 . doi:10.1186/1471-2407-13-174


Author Loh, Yan Ni
Hedditch, Ellen L.
Baker, Laura A.
Jary, Eve
Ward, Robyn L.
Ford, Caroline E.
Title The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer
Formatted title
The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer
Journal name BMC Cancer   Check publisher's open access policy
ISSN 1471-2407
Publication date 2013-04-02
Year available 2013
Sub-type Article (original research)
DOI 10.1186/1471-2407-13-174
Open Access Status DOI
Volume 13
Total pages 9
Place of publication London, United Kingdom
Publisher BioMed Central
Language eng
Formatted abstract
Background: Acquired resistance to Tamoxifen remains a critical problem in breast cancer patient treatment, yet the underlying causes of resistance have not been fully elucidated. Abberations in the Wnt signalling pathway have been linked to many human cancers, including breast cancer, and appear to be associated with more metastatic and aggressive types of cancer. Here, our aim was to investigate if this key pathway was involved in acquired Tamoxifen resistance, and could be targeted therapeutically.

Methods: An in vitro model of acquired Tamoxifen resistance (named TamR) was generated by growing the estrogen receptor alpha (ER) positive MCF7 breast cancer cell line in increasing concentrations of Tamoxifen (up to 5 uM). Alterations in the Wnt signalling pathway and epithelial to mesenchymal transition (EMT) in response to Tamoxifen and treatment with the Wnt inhibitor, IWP-2 were measured via quantitative RT-PCR (qPCR) and TOP/FOP Wnt reporter assays. Resistance to Tamoxifen, and effects of IWP-2 treatment were determined by MTT proliferation assays.

Results: TamR cells exhibited increased Wnt signalling as measured via the TOP/FOP Wnt luciferase reporter assays. Genes associated with both the β-catenin dependent (AXIN2, MYC, CSNK1A1) and independent arms (ROR2, JUN), as well as general Wnt secretion (PORCN) of the Wnt signalling pathway were upregulated in the TamR cells compared to the parental MCF7 cell line. Treatment of the TamR cell line with human recombinant Wnt3a (rWnt3a) further increased the resistance of both MCF7 and TamR cells to the anti-proliferative effects of Tamoxifen treatment. TamR cells demonstrated increased expression of EMT markers (VIM, TWIST1, SNAI2) and decreased CDH1, which may contribute to their resistance to Tamoxifen. Treatment with the Wnt inhibitor, IWP-2 inhibited cell proliferation and markers of EMT.

Conclusions:
These data support the role of the Wnt signalling pathway in acquired resistance to Tamoxifen. Further research into the mechanism by which activated Wnt signalling inhibits the effects of Tamoxifen should be undertaken. As a number of small molecules targeting the Wnt pathway are currently in pre-clinical development, combinatorial treatment with endocrine agents and Wnt pathway inhibitors may be a useful therapeutic option in the future for a subset of breast cancer patients.
Keyword Breast cancer
Endocrine resistant
Epithelial to mesenchymal transition (EMT)
IWP-2
Tamoxifen resistant
Wnt-signalling
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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