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Role of the focal adhesion protein kindlin-1 in breast cancer growth and lung metastasis

Soraya Sin, Florian Bonin, Valérie Petit, Didier Meseure, François Lallemand, Ivan Bièche, Akeila Bellahcène, Vincent Castronovo, Olivier De Wever UGent and Christian Gespach, et al. (2011) JOURNAL OF THE NATIONAL CANCER INSTITUTE. 103(17). p.1323-1337
abstract
Fermitin family member 1 (FERMT1, Kindlin-1) is an epithelial-specific regulator of integrin functions and is associated with Kindler syndrome, a genetic disorder characterized by skin blistering, atrophy, and photosensitivity. However, the possible role of kindlin-1 in cancer remains unknown. Kindlin-1 expression was quantified in several human cancers using quantitative real-time polymerase chain reaction and published microarray datasets. The association between kindlin-1 expression and patient metastasis-free survival (N = 516) was assessed with Kaplan-Meier analyses. Effects of ectopic expression or silencing of kindlin-1 on cell signaling, migration, and invasion were assessed in human breast cancer cell lines using western blotting, immunofluorescence, wound healing assays, and invasion on Matrigel or type I collagen substrates. Breast tumor growth and lung metastasis were evaluated in 12-week-old female BALB/c mice (10 controls and six Kindlin-1-knockdown mice). All statistical tests were two-sided. Kindlin-1 expression was consistently higher in tumors than in normal tissues in various cancer types metastasizing to the lungs, including colon and bladder cancer. Kindlin-1 expression was associated with metastasis-free survival in both breast and lung adenocarcinoma (breast cancer: hazard ratio of lung metastasis = 2.55, 95% confidence intervals [CI] = 1.39 to 4.69, P = .001; lung cancer: hazard ratio of metastasis = 1.96, 95% CI = 1.25 to 3.07, P = .001). Overexpression of kindlin-1 induced changes indicating epithelial-mesenchymal transition and transforming growth factor beta (TGF beta) signaling, constitutive activation of cell motility, and invasion (number of migrating cells, Kindlin-1 cells vs control, mean = 164.66 vs 19.00, difference = 145.6, 95% CI = 79.1 to 212.2, P = .004; invasion rate, Kindlin-1-cells vs control = 9.65% vs 1.92%, difference = 7.73%, 95% CI = 4.75 to 10.70, P < .001). Finally, Kindlin-1 depletion in an orthotopic mouse model statistically significantly inhibited breast tumor growth (P < .001) and lung metastasis (P = .003). These results suggest a role for kindlin-1 in breast cancer lung metastasis and lung tumorigenesis and advance our understanding of kindlin-1 as a regulator of TGF beta signaling, offering new avenues for therapeutic intervention against cancer progression.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
KINDLER-SYNDROME, GENE-EXPRESSION SIGNATURE, CLINICAL-IMPLICATIONS, TUMOR-METASTASIS, GENOMIC ANALYSIS, PROSTATE-CANCER, MAMMARY-TUMOR, FACTOR-BETA, SURVIVAL, CELLS
journal title
JOURNAL OF THE NATIONAL CANCER INSTITUTE
J. Natl. Cancer Inst.
volume
103
issue
17
pages
1323 - 1337
Web of Science type
Article
Web of Science id
000294814600011
JCR category
ONCOLOGY
JCR impact factor
13.757 (2011)
JCR rank
6/190 (2011)
JCR quartile
1 (2011)
ISSN
0027-8874
DOI
10.1093/jnci/djr290
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2941406
handle
http://hdl.handle.net/1854/LU-2941406
date created
2012-06-28 13:22:28
date last changed
2012-07-09 11:31:33
@article{2941406,
  abstract     = {Fermitin family member 1 (FERMT1, Kindlin-1) is an epithelial-specific regulator of integrin functions and is associated with Kindler syndrome, a genetic disorder characterized by skin blistering, atrophy, and photosensitivity. However, the possible role of kindlin-1 in cancer remains unknown. 
Kindlin-1 expression was quantified in several human cancers using quantitative real-time polymerase chain reaction and published microarray datasets. The association between kindlin-1 expression and patient metastasis-free survival (N = 516) was assessed with Kaplan-Meier analyses. Effects of ectopic expression or silencing of kindlin-1 on cell signaling, migration, and invasion were assessed in human breast cancer cell lines using western blotting, immunofluorescence, wound healing assays, and invasion on Matrigel or type I collagen substrates. Breast tumor growth and lung metastasis were evaluated in 12-week-old female BALB/c mice (10 controls and six Kindlin-1-knockdown mice). All statistical tests were two-sided. 
Kindlin-1 expression was consistently higher in tumors than in normal tissues in various cancer types metastasizing to the lungs, including colon and bladder cancer. Kindlin-1 expression was associated with metastasis-free survival in both breast and lung adenocarcinoma (breast cancer: hazard ratio of lung metastasis = 2.55, 95\% confidence intervals [CI] = 1.39 to 4.69, P = .001; lung cancer: hazard ratio of metastasis = 1.96, 95\% CI = 1.25 to 3.07, P = .001). Overexpression of kindlin-1 induced changes indicating epithelial-mesenchymal transition and transforming growth factor beta (TGF beta) signaling, constitutive activation of cell motility, and invasion (number of migrating cells, Kindlin-1 cells vs control, mean = 164.66 vs 19.00, difference = 145.6, 95\% CI = 79.1 to 212.2, P = .004; invasion rate, Kindlin-1-cells vs control = 9.65\% vs 1.92\%, difference = 7.73\%, 95\% CI = 4.75 to 10.70, P {\textlangle} .001). Finally, Kindlin-1 depletion in an orthotopic mouse model statistically significantly inhibited breast tumor growth (P {\textlangle} .001) and lung metastasis (P = .003). 
These results suggest a role for kindlin-1 in breast cancer lung metastasis and lung tumorigenesis and advance our understanding of kindlin-1 as a regulator of TGF beta signaling, offering new avenues for therapeutic intervention against cancer progression.},
  author       = {Sin, Soraya and Bonin, Florian and Petit, Val{\'e}rie and Meseure, Didier and Lallemand, Fran\c{c}ois and Bi{\`e}che, Ivan and Bellahc{\`e}ne, Akeila and Castronovo, Vincent and De Wever, Olivier and Gespach, Christian and Lidereau, Rosette and Driouch, Keltouma},
  issn         = {0027-8874},
  journal      = {JOURNAL OF THE NATIONAL CANCER INSTITUTE},
  keyword      = {KINDLER-SYNDROME,GENE-EXPRESSION SIGNATURE,CLINICAL-IMPLICATIONS,TUMOR-METASTASIS,GENOMIC ANALYSIS,PROSTATE-CANCER,MAMMARY-TUMOR,FACTOR-BETA,SURVIVAL,CELLS},
  language     = {eng},
  number       = {17},
  pages        = {1323--1337},
  title        = {Role of the focal adhesion protein kindlin-1 in breast cancer growth and lung metastasis},
  url          = {http://dx.doi.org/10.1093/jnci/djr290},
  volume       = {103},
  year         = {2011},
}

Chicago
Sin, Soraya, Florian Bonin, Valérie Petit, Didier Meseure, François Lallemand, Ivan Bièche, Akeila Bellahcène, et al. 2011. “Role of the Focal Adhesion Protein Kindlin-1 in Breast Cancer Growth and Lung Metastasis.” Journal of the National Cancer Institute 103 (17): 1323–1337.
APA
Sin, S., Bonin, F., Petit, V., Meseure, D., Lallemand, F., Bièche, I., Bellahcène, A., et al. (2011). Role of the focal adhesion protein kindlin-1 in breast cancer growth and lung metastasis. JOURNAL OF THE NATIONAL CANCER INSTITUTE, 103(17), 1323–1337.
Vancouver
1.
Sin S, Bonin F, Petit V, Meseure D, Lallemand F, Bièche I, et al. Role of the focal adhesion protein kindlin-1 in breast cancer growth and lung metastasis. JOURNAL OF THE NATIONAL CANCER INSTITUTE. 2011;103(17):1323–37.
MLA
Sin, Soraya, Florian Bonin, Valérie Petit, et al. “Role of the Focal Adhesion Protein Kindlin-1 in Breast Cancer Growth and Lung Metastasis.” JOURNAL OF THE NATIONAL CANCER INSTITUTE 103.17 (2011): 1323–1337. Print.