From the Cover

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

Caroline E. Ford^a,b,1, Elin J. Ekström^a, and Tommy Andersson^a

^aCell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, 20502, Sweden; and ^bIntegrated Cancer Research Group, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia

Received for publication September 23, 2008.

Abstract: One third of all breast cancers are estrogen receptor alpha (ER) 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 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 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-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 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 promoter. Up-regulated ER 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 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 expression in an in vivo model of ER-negative breast cancer. This represents the first evidence that Wnt-5a signaling acts to re-establish ER expression in ER-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-negative breast cancer patients.

Key Words: breast cancer • ER

Conflict of interest statement: C.E.F. and T.A. have filed a patent for the effects of the Foxy-5 peptide on ER.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0809516106/DCSupplemental.

¹To whom correspondence should be addressed. E-mail: caroline.ford{at}med.lu.se

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