Cell and Experimental Pathology
Wnt-5a signaling in breast cancer metastasis
Academic Dissertation by due permission of the Faculy of Medicine, Lund University, Sweden
to be defended at the main lecture hall, Pathlogy building, Malmö University Hospital , Malmö
on Friday 23rd of November, 2007 at 9,15
for the degree of Doctor of Philosophy,
Faculty of Medicine
Faculty opponent: Professor Randall Moon,
Howard Hughes Medical Insitute,
Department of Pharmacology,
Institute of Stem Cell and Regenerative Medicine,
University of Washington School of Medicine,
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.