Kindlin‐3 enhances breast cancer progression and metastasis by activating Twist‐mediated angiogenesis

Abstract

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.

Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity

“…Kindlin-3 is expressed primarily in white blood cells; its loss of function is associated with leukocyte attachment deficiency (LAD) (38). Overexpression of Kindlins has been detected frequently in human cancers (39)(40)(41). We focused on the function of kindlin-2 in fibroblasts, as they control the production of many extracellular matrix proteins.…”

The kindlin family: functions, signaling properties and implications for human disease

“…The comparison of the human and mouse genomes revealed the existence of three Mig-2/kindlin isoforms (Siegel et al, 2003), and expression analyses revealed that the three Mig-2/kindlin family members are expressed in different cells and tissues (Ussar et al, 2006). Kindlin-1 is mainly expressed in epithelial cells, kindlin-2 is broadly expressed but absent in all blood cells analyzed so far (Ussar et al, 2006), and kindlin-3 is found in hematopoietic cells and, possibly, also at low levels in endothelial cells and in solid cancers, such as breast cancer and melanoma (Sossey-Alaoui et al, 2014;Djaafri et al, 2014;Delyon et al, 2015). It is unclear whether the expression of kindlin-3 in solid tumors is caused by de novo activation of the KINDLIN-3 gene or by infiltration of hematopoietic cells.…”

Site-specific Phosphorylation of Kindlin-3 Protein Regulates Its Capacity to Control Cellular Responses Mediated by Integrin αIIbβ3

“…Kindlin-3 mutations in have been identified in humans with a rare syndrome referred to as LADIII (21)(22)(23)(24)(25) with manifestations that include episodic bleeding, susceptibility to frequent infections and osteopetrosis, which are consequences of an inability to activate ␤ 1 , ␤ 2 and ␤ 3 integrin (22,23,25), and variably in abnormal red cell shapes (25). Kindlin-3 is also present and functional in endothelial cells (26) and breast cancer cells (27), where it acts as a tumor promoter (27). Despite this ample evidence emphasizing the role of kindlin-3 in integrin function in variety of cells, the mechanisms underlying kindlin-mediated integrin activation are largely unknown.…”