被撤回的出版物: Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells (Retracted Article. See vol 107, pg 22360, 2010)

One third of all breast cancers are estrogen receptor alpha (ER alpha) negative, carry 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 previously been correlated with loss of ER alpha in clinical breast cancer samples, and we sought to investigate this association further. Three breast cancer cell lines (MDA-MB-231, MDA-MB-468, and 4T1) lacking expression of ER alpha and Wnt-5a, and one breast cancer cell line (T47D) expressing both proteins were used in this study. Wnt-5a signaling was generated in ER alpha-negative cell lines via stimulation with either recombinant Wnt-5a protein or a Wnt-5a-derived hexapeptide (Foxy-5) possessing Wnt-5a signaling properties. ER alpha expression was restored at both mRNA and protein level, after treatment with recombinant Wnt-5a or Foxy-5. This restoration of expression occurred in parallel with a reduction in methylation of the ER alpha promoter. Up-regulated ER alpha could be activated, initiate transcription of progesterone receptor and pS2, and activate an estrogen response element reporter construct. Significantly, breast cancer cells re-expressing ER alpha responded to treatment with the selective estrogen receptor modulator tamoxifen, as measured by induction of apoptosis and cell growth inhibition. Finally, Foxy-5 also increased ER alpha expression in an in vivo model of ER alpha-negative breast cancer. This represents the first evidence that Wnt-5a signaling acts to re-establish ER alpha expression in ER alpha-negative breast cancer cells. Our data suggest that combinatorial therapy with Foxy-5 and tamoxifen should be considered as a future treatment possibility for ER alpha-negative breast cancer patients.