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PNAS 106 (10): 3919-3924

Copyright © 2009 by the National Academy of Sciences.

From the Cover


BIOLOGICAL SCIENCES / MEDICAL SCIENCES

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

Caroline E. Forda,b,1, Elin J. Ekströma, and Tommy Anderssona

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

Edited by Jan-Åke Gustafsson, Karolinska Institutet, Stockholm, Sweden, and approved January 8, 2009

Received for publication September 23, 2008.

Abstract: 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.

Key Words: breast cancer • ER


Author contributions: C.E.F., E.J.E., and T.A. designed research; C.E.F. and E.J.E. performed research; C.E.F., E.J.E., and T.A. analyzed data; and C.E.F. and T.A. wrote the paper.

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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