Role of the Focal Adhesion Protein Kindlin-1 in Breast Cancer Growth and Lung Metastasis.

[en] Background 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. Methods 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. Results 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 (TGFbeta) 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). Conclusion 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 TGFbeta signaling, offering new avenues for therapeutic intervention against cancer progression.

Research Center/Unit :

Giga-Cancer - ULiège

Disciplines :

Oncology

Author, co-author :

Sin, S.

Bonin, F.

Petit, V.

Meseure, D.

Lallemand, F.

Bieche, I.

Bellahcene, Akeila ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases

Castronovo, Vincenzo ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire

de Wever, O.

Gespach, C.

Lidereau, R.

Driouch, K.

Language :

English

Title :

Role of the Focal Adhesion Protein Kindlin-1 in Breast Cancer Growth and Lung Metastasis.

Publication date :

2011

Journal title :

Journal of the National Cancer Institute

ISSN :

0027-8874

eISSN :

1460-2105

Publisher :

Oxford University Press, Cary, United States - North Carolina

Volume :

103

Pages :

1-15

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

BCRF - Breast Cancer Research Foundation [US-NY] [US-NY]
Région Île-de-France [FR]
ARC - Association pour la Recherche sur le Cancer [FR]

Funding text :

European Commission Framework Program VI METABRE

Available on ORBi :

since 26 October 2011

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