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

Ford, Caroline LU ; Ekström, Elin LU and Andersson, Tommy LU (2009) In Proceedings of the National Academy of Sciences Feb 23. p.3919-3924
Abstract
One third of all breast cancers are estrogen receptor alpha (ERalpha) 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 ERalpha 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 ERalpha and Wnt-5a, and one breast cancer cell line (T47D) expressing both proteins were used in this study. Wnt-5a signaling was generated in ERalpha-negative cell lines via stimulation with either recombinant Wnt-5a protein or a Wnt-5a-derived hexapeptide (Foxy-5)... (More)
One third of all breast cancers are estrogen receptor alpha (ERalpha) 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 ERalpha 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 ERalpha and Wnt-5a, and one breast cancer cell line (T47D) expressing both proteins were used in this study. Wnt-5a signaling was generated in ERalpha-negative cell lines via stimulation with either recombinant Wnt-5a protein or a Wnt-5a-derived hexapeptide (Foxy-5) possessing Wnt-5a signaling properties. ERalpha 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 ERalpha promoter. Up-regulated ERalpha could be activated, initiate transcription of progesterone receptor and pS2, and activate an estrogen response element reporter construct. Significantly, breast cancer cells re-expressing ERalpha 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 ERalpha expression in an in vivo model of ERalpha-negative breast cancer. This represents the first evidence that Wnt-5a signaling acts to re-establish ERalpha expression in ERalpha-negative breast cancer cells. Our data suggest that combinatorial therapy with Foxy-5 and tamoxifen should be considered as a future treatment possibility for ERalpha-negative breast cancer patients. (Less)
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organization
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type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
Feb 23
pages
3919 - 3924
publisher
National Acad Sciences
external identifiers
  • wos:000264036900050
  • pmid:19237581
  • scopus:62649157723
ISSN
1091-6490
DOI
10.1073/pnas.0809516106
language
English
LU publication?
yes
id
6a889ff4-7919-464f-a36c-27ad59efc6a3 (old id 1302267)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19237581?dopt=Abstract
date added to LUP
2009-03-03 12:02:13
date last changed
2017-01-01 07:39:32
@article{6a889ff4-7919-464f-a36c-27ad59efc6a3,
  abstract     = {One third of all breast cancers are estrogen receptor alpha (ERalpha) 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 ERalpha 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 ERalpha and Wnt-5a, and one breast cancer cell line (T47D) expressing both proteins were used in this study. Wnt-5a signaling was generated in ERalpha-negative cell lines via stimulation with either recombinant Wnt-5a protein or a Wnt-5a-derived hexapeptide (Foxy-5) possessing Wnt-5a signaling properties. ERalpha 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 ERalpha promoter. Up-regulated ERalpha could be activated, initiate transcription of progesterone receptor and pS2, and activate an estrogen response element reporter construct. Significantly, breast cancer cells re-expressing ERalpha 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 ERalpha expression in an in vivo model of ERalpha-negative breast cancer. This represents the first evidence that Wnt-5a signaling acts to re-establish ERalpha expression in ERalpha-negative breast cancer cells. Our data suggest that combinatorial therapy with Foxy-5 and tamoxifen should be considered as a future treatment possibility for ERalpha-negative breast cancer patients.},
  author       = {Ford, Caroline and Ekström, Elin and Andersson, Tommy},
  issn         = {1091-6490},
  language     = {eng},
  pages        = {3919--3924},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells.},
  url          = {http://dx.doi.org/10.1073/pnas.0809516106},
  volume       = {Feb 23},
  year         = {2009},
}