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The Wnt-5a-derived hexapeptide Foxy-5 inhibits breast cancer metastasis in vivo by targeting cell motility.

AbstractPURPOSE:
An inherent problem in breast cancer treatment is that current therapeutic approaches fail to specifically target the dissemination of breast cancer cells from the primary tumor. Clinical findings show that the loss of Wnt-5a protein expression in the primary breast tumor predicts a faster tumor spread, and in vitro analyses reveal that it does so by inhibiting tumor cell migration. Therefore, we hypothesized that the reconstitution of Wnt-5a signaling could be a novel therapeutic strategy to inhibit breast cancer metastasis.
EXPERIMENTAL DESIGN:
We used in vitro techniques to show that 4T1 mouse breast cancer cells responded to the reconstitution of Wnt-5a signaling using our novel Wnt-5a mimicking hexapeptide, Foxy-5, in the same way as human breast cancer cells. Therefore, we could subsequently study its effect in vivo on the metastatic spread of cancer following the inoculation of 4T1 cells into mice.
RESULTS:
In vitro analyses revealed that both recombinant Wnt-5a and the Wnt-5a-derived Foxy-5 peptide impaired migration and invasion without affecting apoptosis or proliferation of 4T1 breast cancer cells. The in vivo experiments show that i.p. injections of Foxy-5 inhibited metastasis of inoculated 4T1 breast cancer cells from the mammary fat pad to the lungs and liver by 70% to 90%.
CONCLUSIONS:
These data provide proof of principle that the reconstitution of Wnt-5a signaling in breast cancer cells is a novel approach to impair breast tumor metastasis by targeting cell motility. In combination with existing therapies, this approach represents a potential novel therapeutic strategy for the treatment of breast cancer patients.
AuthorsAnnette Säfholm, Johanna Tuomela, Jeanette Rosenkvist, Janna Dejmek, Pirkko Härkönen, Tommy Andersson
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 20 Pg. 6556-63 (Oct 15 2008) ISSN: 1078-0432 [Print] United States
PMID18927296 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • WNT5A protein, human
  • Wnt Proteins
  • Wnt-5a Protein
Topics
  • Animals
  • Apoptosis (physiology)
  • Breast (metabolism, pathology)
  • Breast Neoplasms (metabolism, pathology, therapy)
  • Cell Movement (drug effects)
  • Cell Proliferation
  • Cells, Cultured
  • Female
  • Humans
  • In Situ Nick-End Labeling
  • Liver Neoplasms (metabolism, secondary, therapy)
  • Lung Neoplasms (metabolism, secondary, therapy)
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Invasiveness
  • Peptide Fragments (immunology, metabolism, therapeutic use)
  • Proto-Oncogene Proteins (immunology, metabolism)
  • Wnt Proteins (immunology, metabolism)
  • Wnt-5a Protein

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