Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor negative breast cancer cells.

A17 One third of all breast cancers are estrogen receptor alpha (ERα) negative, have a poor overall prognosis and do not respond well to currently available endocrine therapies. New treatment strategies are therefore required. Loss of Wnt-5a has been correlated with loss of ERα expression in clinical breast cancer samples. Therefore, we sought to further investigate the association between ERα and Wnt-5a in breast cancer.
 Three breast cancer cell lines (MDA-MB-231, MDA-MB-468 and 4T1) lacking endogenous expression of ERα and Wnt-5a, and one breast cancer cell line (MCF7) expressing both proteins were utilized in this study. Wnt-5a signaling was generated in these cells via stimulation with either recombinant Wnt-5a protein (rW5a) or a Wnt-5a derived hexapeptide (Foxy-5) possessing properties of Wnt-5a signaling. ERα expression was restored at both mRNA and protein levels following treatment with rW5a or Foxy-5. Upregulated ERα was also active, as measured by Ser118 phosphorylation and capable of downstream transcription of progesterone receptor. Most significantly, breast cancer cells re-expressing ERα responded to treatment with the selective estrogen receptor modulator Tamoxifen, as measured by induction of apoptosis.
 This represents the first evidence that Wnt-5a signaling acts to re-establish ERα expression in ER-negative breast cancer cells. Our data suggests that combinatorial therapy with Foxy-5 and Tamoxifen should be considered as a future treatment possibility for ER-negative breast cancer patients.