title: 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).
  
  
  CONCLUSIONS
  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.affiliation: Institut Curie, Laboratoire d'Oncogénétique, Hôpital René Huguenin, 35 rue Dailly, Saint-Cloud, 92210, France.
authors.forename: Soraya
authors.initials: S
authors.lastname: Sin
authors.forename: Florian
authors.initials: F
authors.lastname: Bonin
authors.forename: Valérie
authors.initials: V
authors.lastname: Petit
authors.forename: Didier
authors.initials: D
authors.lastname: Meseure
authors.forename: François
authors.initials: F
authors.lastname: Lallemand
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.forename: Akeila
authors.initials: A
authors.lastname: Bellahcène
authors.forename: Vincent
authors.initials: V
authors.lastname: Castronovo
authors.forename: Olivier
authors.initials: O
authors.lastname: de Wever
authors.forename: Christian
authors.initials: C
authors.lastname: Gespach
authors.forename: Rosette
authors.initials: R
authors.lastname: Lidereau
authors.forename: Keltouma
authors.initials: K
authors.lastname: Driouch
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000556:secondary; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D005455:Fluorescent Antibody Technique; D022001:Focal Adhesions / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C475301:FERMT1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta