Tamoxifen is an effective drug in the treatment of breast cancer. It binds to estrogen receptor α (ERα), decreasing the expression of ERα target genes, reducing cell proliferation, and inducing apoptosis. Many breast cancers are ERα-negative, however, and so are unresponsive to tamoxifen, which has stimulated the search for alternative therapies. Noting that loss of ERα in breast cancer cells correlates with the loss of the secreted glycoprotein Wnt-5a, Ford et al. treated ERα-negative breast cancer cells and cell lines with recombinant Wnt-5a and found that expression of ERα 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 ERα in breast cancer cells is associated with hypermethylation of the promoter of the gene encoding ERα. ERα-negative cells treated with Wnt-5a or Foxy-5 showed reduced methylation at the ERα promoter compared with that in untreated ERα-negative cells. The ERα ligand estradiol triggered the phosphorylation of ERα in a cancer cell line treated with Wnt-5a or Foxy-5, and reporter assays and Western blotting analysis of ERα targets showed that the restored ERα was functional. Restoration of ERα 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 ERα in breast tumor cells, whereas a control peptide did not. The authors suggest that Foxy-5 may have therapeutic potential in the treatment of ERα-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]