Kindlin-3 enhances breast cancer progression and metastasis by activating Twist-mediated angiogenesis.
The FERM domain containing protein Kindlin-3 has been recognized as a major regulator of integrin function in hematopoietic cells, but its role in neoplasia is totally unknown. We have examined the relationship between Kindlin-3 and breast cancer in mouse models and human tissues. Human breast tumors showed a ∼7-fold elevation in Kindlin-3 mRNA compared with nonneoplastic tissue by quantitative polymerase chain reaction. Kindlin-3 overexpression in a breast cancer cell line increased primary tumor growth and lung metastasis by 2.5- and 3-fold, respectively, when implanted into mice compared with cells expressing vector alone. Mechanistically, the Kindlin-3-overexpressing cells displayed a 2.2-fold increase in vascular endothelial growth factor (VEGF) secretion and enhanced β1 integrin activation. Increased VEGF secretion resulted from enhanced production of Twist, a transcription factor that promotes tumor angiogenesis. Knockdown of Twist diminished VEGF production, and knockdown of β1 integrins diminished Twist and VEGF production by Kindlin-3-overexpressing cells, while nontargeting small interfering RNA had no effect on expression of these gene products. Thus, Kindlin-3 influences breast cancer progression by influencing the crosstalk between β1 integrins and Twist to increase VEGF production. This signaling cascade enhances breast cancer cell invasion and tumor angiogenesis and metastasis.
2Department of Molecular Cardiology, Cleveland Clinic Lerner Research Institute, 9500 Euclid Ave. NB50, Cleveland, OH 44195, USA. E.F.P., plowe@ccf.org.
Khalid
K
Sossey-Alaoui
Elzbieta
E
Pluskota
Gangarao
G
Davuluri
Katarzyna
K
Bialkowska
Mitali
M
Das
Dorota
D
Szpak
Daniel J
DJ
Lindner
Erinn
E
Downs-Kelly
Cheryl L
CL
Thompson
Edward F
EF
Plow
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D019012:Integrin beta1; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D051879:Twist-Related Protein 1; D042461:Vascular Endothelial Growth Factor A; C477322:FERMT3 protein, human; C103173:TWIST1 protein, human; C467484:VEGFA protein, human; C508053:ERBB2 protein, human
VEGF; VEGFR2; epithelial-to-mesenchymal-transition; integrins; tumor macrophages