Advanced

Wnt-5a signaling in breast cancer metastasis

Säfholm, Annette LU (2007) In Lund University Faculty of Medicine Doctoral Dissertation Series
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor Moon, Randall, Howard Hughes Madical Institute, Dept of Pharmacology, Inst for Stem Cell and Regererative Medicine,
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Patologi (allmän), patologisk anatomi, General pathology, cancer, onkologi, Cytologi, breast cancer, Wnt-5a, migration, pathological anatomy, metastasis, signal transduction, peptides, Cytology, cancerology, oncology
in
Lund University Faculty of Medicine Doctoral Dissertation Series
pages
142 pages
publisher
Division of Experimental Pathology, Department of Laboratory Medicine Malmö
defense location
Föreläsningssalen, Patologi-huset, ingång 78, Universitetssjukhuset MAS, Malmö.
defense date
2007-11-23 09:15
ISSN
1652-8220
ISBN
978-91-85897-28-5
language
English
LU publication?
yes
id
f5151826-00fc-40fc-8b7f-63a3e0b0ae69 (old id 599219)
date added to LUP
2007-11-13 08:58:07
date last changed
2016-09-19 08:44:56
@phdthesis{f5151826-00fc-40fc-8b7f-63a3e0b0ae69,
  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.<br/><br>
<br/><br>
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.<br/><br>
<br/><br>
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.},
  author       = {Säfholm, Annette},
  isbn         = {978-91-85897-28-5},
  issn         = {1652-8220},
  keyword      = {Patologi (allmän),patologisk anatomi,General pathology,cancer,onkologi,Cytologi,breast cancer,Wnt-5a,migration,pathological anatomy,metastasis,signal transduction,peptides,Cytology,cancerology,oncology},
  language     = {eng},
  pages        = {142},
  publisher    = {Division of Experimental Pathology, Department of Laboratory Medicine Malmö},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {Wnt-5a signaling in breast cancer metastasis},
  year         = {2007},
}