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

Abstract

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 (TGFβ) 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 TGFβ signaling, offering new avenues for therapeutic intervention against cancer progression.

• Authors: Soraya Sin, Florian Bonin, Valérie Petit, Didier Meseure, François Lallemand, Ivan Bièche, Akeila Bellahcène, Vincent Castronovo, Olivier de Wever, Christian Gespach, Rosette Lidereau, Keltouma Driouch
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 103 Issue 17 Pg. 1323-37 (Sep 07 2011) ISSN: 1460-2105 [Electronic] United States
• PMID: 21832234 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• FERMT1 protein, human
• Membrane Proteins
• Neoplasm Proteins
• RNA, Small Interfering
• Transforming Growth Factor beta

Topics

• Adenocarcinoma (metabolism, secondary)
• Animals
• Biomarkers, Tumor (genetics, metabolism)
• Blotting, Western
• Breast Neoplasms (metabolism, pathology)
• Cell Proliferation
• Female
• Fluorescent Antibody Technique
• Focal Adhesions (metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Lung Neoplasms (metabolism, secondary)
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Neoplasm Proteins (genetics, metabolism)
• Predictive Value of Tests
• Prognosis
• Proportional Hazards Models
• RNA, Small Interfering (metabolism)
• Signal Transduction
• Transforming Growth Factor beta (metabolism)
• Up-Regulation