Distinct expression profiles and functions of Kindlins in breast cancer

Abstract

BackgroundKindlin-1, − 2, and − 3 are the three members of the Kindlin family. They are best known as regulators of integrin functions, contributing to fundamental biological processes such as cell survival, adhesion and migration. Their deregulation leads to diverse pathologies including a broad range of cancers in which both, tumor-promoting and tumor-inhibiting functions have been described.MethodsTo better characterize Kindlins implication in breast cancer, in vitro experiments were performed in a series of cancer cell lines. We first assessed their expression profiles and subcellular distributions. Then, their involvement in breast cancer cell morphology, migration and invasion was verified by examining phenotypic changes induced by the depletion of either isoforms using RNA interference. An expression study was performed in a series of breast cancer patient derived xenografts (n = 58) to define the epithelial and stromal contribution of each Kindlin. Finally, we analyzed the expression levels of the three Kindlins in a large series of human breast tumors, at the RNA (n = 438) and protein (n = 129) levels and we evaluated their correlation with the clinical outcome.ResultsWe determined that Kindlin-1 and Kindlin-2, but not Kindlin-3, were expressed in breast tumor cells. We uncovered the compensatory roles of Kindlin-1 and -2 in focal adhesion dynamics and cell motility. Remarkably, Kindlin-2 had a predominant effect on cell spreading and Kindlin-1 on cell invasion. In line with these experimental observations, Kindlin-1 overexpression was associated with a worse patients’ outcome. Notably, Kindlin-3, expressed by tumor infiltrating leukocytes, also correlated with a poor prognosis of breast cancer patients.ConclusionThis study demonstrates that each one of the Kindlin family members has a different expression profile emphasizing their redundant and complementary roles in breast tumor cells. We highlight the specific link between Kindlin-1 and breast cancer progression. In addition, Kindlin-3 overexpression in the tumor microenvironment is associated with more aggressive breast tumors.These results suggest that Kindlins play distinctive roles in breast cancer. Kindlins may be useful in identifying breast cancer patients with a worst prognosis and may offer new avenues for therapeutic intervention against cancer progression.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0955-4) contains supplementary material, which is available to authorized users.

High Throughput Transcriptome Data Analysis and Computational Verification Reveal Immunotherapy Biomarkers of Compound Kushen Injection for Treating Triple-Negative Breast Cancer

“…Conversely, this gene is also found to enhance breast cancer progression and metastasis by activating Twistmediated angiogenesis (72). Moreover, FERMT3 expressed in the TME is correlated with a poor prognosis of breast cancer patients (73), which is inconsistent with our finding that FERMT3 could serve as a protective prognostic factor in TNBC. These results highlight the complex role of FERMT3 which could exhibit dual effects, so the prognostic value of this gene in breast cancer deserve more attention.…”

Site-specific phosphorylation regulates the functions of kindlin-3 in a variety of cells

“…Kindlin-3 overexpression in a BC cell line increased primary tumor growth and lung metastasis and mechanistically, kindlin-3overexpressing cells displayed a marked increase in VEGF secretion, which was dependent upon enhanced expression of the Twist transcription factor (Sossey-Alaoui et al, 2014) and enhanced β 1 integrin activation. The association of kindlin-3 with BC has been corroborated by some studies (Djaafri et al, 2014), although not all other studies (Azorin et al, 2018). In the present work, we establish that kindlin-3 phosphorylation is crucial for kindlin-3 function in BC cells and other cell types, including platelets, megakaryocytes, and human erythroleukemia (HEL) megakaryocytic-like cells.…”

Differences in self-association between kindlin-2 and kindlin-3 are associated with differential integrin binding

“…kindlin-2 and kindlin-3 can self-associate roles of kindlin-3 self-association in hematopoietic cells, endothelial cells, and breast cancer cells that express endogenous kindlin-3 (36)(37)(38). In light of our findings that kindlin self-association inversely correlates with integrin binding, it will be important to test the consequences of selectively modulating kindlin-3 selfassociation on cell adhesion and spreading and integrin activation and signaling in these cells.…”