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Sci. Signal., 17 March 2009
Vol. 2, Issue 62, p. ec94
[DOI: 10.1126/scisignal.262ec94]


Cancer Therapy Back to the Dead

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Tamoxifen is an effective drug in the treatment of breast cancer. It binds to estrogen receptor {alpha} (ER{alpha}), decreasing the expression of ER{alpha} target genes, reducing cell proliferation, and inducing apoptosis. Many breast cancers are ER{alpha}-negative, however, and so are unresponsive to tamoxifen, which has stimulated the search for alternative therapies. Noting that loss of ER{alpha} in breast cancer cells correlates with the loss of the secreted glycoprotein Wnt-5a, Ford et al. treated ER{alpha}-negative breast cancer cells and cell lines with recombinant Wnt-5a and found that expression of ER{alpha} mRNA and protein was restored. Similar results were obtained with a Wnt-5a–derived hexapeptide called Foxy-5, which shares signaling properties with Wnt-5a. Loss of ER{alpha} in breast cancer cells is associated with hypermethylation of the promoter of the gene encoding ER{alpha}. ER{alpha}-negative cells treated with Wnt-5a or Foxy-5 showed reduced methylation at the ER{alpha} promoter compared with that in untreated ER{alpha}-negative cells. The ER{alpha} ligand estradiol triggered the phosphorylation of ER{alpha} in a cancer cell line treated with Wnt-5a or Foxy-5, and reporter assays and Western blotting analysis of ER{alpha} targets showed that the restored ER{alpha} was functional. Restoration of ER{alpha} in these cells also rendered them sensitive to tamoxifen-induced cell death, whereas in the absence of Wnt-5a or Foxy-5 the cells were unresponsive. Finally, when administered to mice that had been injected with a breast cancer cell line, Foxy-5 induced the mRNA for ER{alpha} in breast tumor cells, whereas a control peptide did not. The authors suggest that Foxy-5 may have therapeutic potential in the treatment of ER{alpha}-negative breast tumors by rendering them sensitive to tamoxifen.

C. E. Ford, E. J. Ekström, T. Andersson, Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells. Proc. Natl. Acad. Sci. U.S.A. 106, 3919–3924 (2009). [Abstract] [Full Text]

Citation: J. F. Foley, Back to the Dead. Sci. Signal. 2, ec94 (2009).

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