Wnt-5a signaling in breast cancer metastasis

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Breast cancer is the most common form of malignancy affecting women in the Western world. Today, anticancer treatment can control primary breast tumors, but treatment and prevention of metastatic disease still represents a major challenge in the management of breast cancer patients. It has been shown that Wnt-5a plays an important role in breast cancer, since loss of that protein is associated with a higher frequency of metastasis.

The findings presented in this thesis show that Wnt-5a inhibits the metastatic behaviour of breast cancer cells by blocking Ca2+-induced NFAT activation. This inhibition is mediated through activation of Yes, Cdc42 and CK1?. Furthermore, based on sequence analysis of the Wnt-5a protein, I identified two peptides with Wnt-5a mimicking ability. One of the peptides was shortened and modified to yield the formylated hexapeptide, Foxy-5, which was able to copy the effects of Wnt-5a on the intracellular signaling, adhesion and migration of breast epithelial cells.

Experiments were performed in which the mammary fat pads of athymic (immunodeficient) BALB/c mice and normal BALB/c mice were inoculated with 4T1 breast cancer cells. Administration of Foxy-5 every fourth day did not lead to any difference in primary tumor growth, whereas it did radically reduce the level of metastasis to lung and liver compared to controls. The mechanism behind the inhibited metastasis formation seemed to be impaired migration and invasion in the breast cancer cells. In addition, the Wnt-5a coreceptor Ror2 was found to be involved in regulation of breast cancer cell migration and to associate with DDR1, a tyrosine kinase receptor that participates in Wnt-5a signaling. These results further emphasize the importance of Wnt-5a in breast cancer metastasis, and they identify a novel potential treatment strategy.

Details

Authors
  • Annette Säfholm
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • Patologi (allmän), patologisk anatomi, General pathology, cancer, onkologi, Cytologi, breast cancer, Wnt-5a, migration, pathological anatomy, metastasis, signal transduction, peptides, Cytology, cancerology, oncology
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2007 Nov 23
Publisher
  • Division of Experimental Pathology, Department of Laboratory Medicine Malmö
Print ISBNs978-91-85897-28-5
Publication statusPublished - 2007
Publication categoryResearch

Bibliographic note

Defence details Date: 2007-11-23 Time: 09:15 Place: Föreläsningssalen, Patologi-huset, ingång 78, Universitetssjukhuset MAS, Malmö. External reviewer(s) Name: Moon, Randall Title: professor Affiliation: Howard Hughes Madical Institute, Dept of Pharmacology, Inst for Stem Cell and Regererative Medicine, ---

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Related research output

Annette Säfholm, Karin Leandersson, Janna Sand-Dejmek, Christian Kamp-Nielsen, Bruno O Villoutreix & Tommy Andersson, 2006, In: Journal of Biological Chemistry. 281, 5, p. 2740-2749

Research output: Contribution to journalArticle

Janna Sand-Dejmek, Annette Säfholm, Christian Kamp-Nielsen, Tommy Andersson & Karin Leandersson, 2006, In: Molecular and Cellular Biology. 26, 16, p. 6024-6036

Research output: Contribution to journalArticle

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