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

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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.
Keywords
KINDLER-SYNDROME, GENE-EXPRESSION SIGNATURE, CLINICAL-IMPLICATIONS, TUMOR-METASTASIS, GENOMIC ANALYSIS, PROSTATE-CANCER, MAMMARY-TUMOR, FACTOR-BETA, SURVIVAL, CELLS

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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.
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.
Chicago author-date
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.
Chicago author-date (all authors)
Sin, Soraya, Florian Bonin, Valérie Petit, Didier Meseure, François Lallemand, Ivan Bièche, Akeila Bellahcène, Vincent Castronovo, Olivier De Wever, Christian Gespach, Rosette Lidereau, and Keltouma Driouch. 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.
IEEE
[1]
S. Sin et al., “Role of the focal adhesion protein kindlin-1 in breast cancer growth and lung metastasis,” JOURNAL OF THE NATIONAL CANCER INSTITUTE, vol. 103, no. 17, pp. 1323–1337, 2011.
@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 < .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.},
  author       = {Sin, Soraya and Bonin, Florian and Petit, Valérie and Meseure, Didier and Lallemand, François and Bièche, Ivan and Bellahcène, 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},
  keywords     = {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},
}

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