Table 1.
Summary of studies investigating the role of ILK in BC using in vitro, and in vivo models as well as human patient samples.
| Study | In vitro | In vivo | Human BC samples | Experimental design | Functional effect | Signaling |
|---|---|---|---|---|---|---|
| [32] | √ | Overexpression of ILK in MDA-MB-231 and MDA-MB-435 BC cells | Suppression of anoikis which is reversible by transfection of dominant negative kinase dead ILK | |||
| [47] | √ | Inhibition of ILK by QLT-0267 in MDA-MB-231 cells | BC cell apoptosis | Reduced mTOR expression and PKB/Akt Ser473 phosphorylation | ||
| [44] | √ | ILK attenuation either via silencing or through pharmacological inhibition | ILK overexpression promotes cell migration | -Hyperphosphorylation of ERα | ||
| [48] | √ | ILK attenuation either via silencing or through pharmacological inhibition in MDA-MB-231 cells | -Inhibition of cell invasion | -Blocking of Akt, ERK, c-Jun, and uPA. | ||
| [22] | √ | Depletion of ILK and Rictor in MDA-MB-231 cells | BC cell apoptosis | -ILK binds to Rictor -Inhibition of Akt Ser473 phosphorylation |
||
| [51] | √ | -ILK overexpression -ILK inhibition by QLT-0267 -ILK silencing in 6 BC cell lines (LCC6Her2, MCF7Her2, SKBR3, ΒΤ474, JIMT-1, KPL-4) |
ILK regulates Akt Ser473 phosphorylation, YB-1 expression and promoter activity, and Twist expression. | |||
| [52] | √ | -Suppression of ILK by ILK inhibitor T315 or gene silencing in MDA-MB-468 cells -Rictor silencing |
- ILK or Rictor silencing inhibits phosphorylation of Ser473-Akt | |||
| [35] | √ | -ILK inhibition in BC cells MCF10A and MDA-MB-231 cells | - Suppression of ILK suppresses EMT | ILK suppresses Hippo pathway (MST1, LATS1) and promotes YAP/TAZ | ||
| [40] | √ | -Overexpression of Twist or integrin β1 in MCF10A breast epithelial cells and TRAQ-labeling combined with 2D LC-MS/MS analysis. -Twist, ILK, or integrin β1 silencing in BT549 and Hs578T |
-Twist or integrin β1 silencing reduces ILK and impairs EMT and cell invasion. -ILK silencing suppresses Twist mediated EMT and invasion |
-integrin β1 or Twist overexpression regulates ILK | ||
| [16] | √ | -ILK overexpression in MCF-7 cells -ILK silencing in MDA-MB-231 cells |
-ILK overexpression results in cell growth and proliferation. | -Through PI3K/Akt pathway | ||
| [57] | √ | Transgenic mice overexpressing ILK under the MMTV promoter | Tumorigenicity and tumor hyperplasia. | -Induction of PKB/Akt, GSK-3β and ERK phosphorylation. | ||
| [60] | √ | √ | -Overexpression of ILK in MDA-MB-435 cells (ILK deficient) and in vivo in athymic nude mice | -Reduction in proliferation, migration, and tumor formation and metastasis in nude mice. -ILK is downregulated in metastatic BC cells →ILK deficiency facilitates neoplastic growth and metastasis |
-Through its ability to block cell cycle progression in G1 phase by blocking integrins | |
| [49] | √ | √ | - Use of ILK inhibitor QLT0267 alone or in combination with chemotherapy drugs. -In vitro in 7 BC cell lines ((LCC6, LCC6Her2, SKBR-3, KPL-4, BT-474, MBA-MB-468, and MCF-7) -In vivo using orthotopic xenografts from low Her2-expressing cells (LCC6) |
-Docetaxel had synergistic action with QLT0267 resulting in increased cytotoxicity and improved therapy. Other chemotherapy drugs had antagonistic effects. - increased survival in the three models and reduction in the growth of cancer cells. |
-Through PI3K/Akt pathway | |
| [39] | √ | √ | -Conditional ILK knock out mice from the mammary epithelium -Inhibition of ILK by an ILK inhibitor or siRNA-mediated silencing in ErbB2-expressing primary mammary gland cells |
-Delay in tumor growth -Induction of apoptosis and reduced cell invasion |
||
| [38] | √ | -Transgenic mice expressing both Wnt and ILK in mammary epithelium (under the MMTV promoter) | -Tumor formation and growth is accelerated -Cooperation between ILK and Wnt in BC |
Elevated expression of Wnt/ILK targets (beta-catenin and cyclin D1) as well as activation of FOXA1 transcription factor, a marker of differentiated mammary luminal cells. | ||
| [55] | √ | √ | -Ectopic expression or shRNA silencing or pharmacological inhibition (via T315) of ILK in MDA-MB-231, SUM-159, MCF-7, MCF-7-IL6 cells -In vivo effect of T315-induced ILK inhibition on CSCs in SUM-159 xenograft models |
- ILK silencing inhibits CSC population in vivo | -ILK regulates IL-6-driven Notch1 activation and CSCs through gamma-secretase components. | |
| [43] | √ | √ | -Overexpression of PARVB in cell lines MCF-7 and MDA-MB-231 -Gene expression analysis in human samples |
-Reduction of cell invasion and anchorage-independent cell growth -Downregulation of PARVB and upregulation of ILK in a significant percentage of BC tumors |
-ParvB inhibits ILK and EGF-induced phosphorylation of ILK cellular targets. | |
| [45] | √ | √ | -Tissue biopsy array consisting of 10 BC biopsy samples | Co-localization of ILK and HIF in human BC samples | ||
| [54] | √ | √ | - ILK depletion via shRNA-mediated silencing and ectopic expression in MDA-MB-231 cells -ILK depletion in ovo |
- In BC samples, ECM stiffness, ILK, and CSC markers (CD44) are associated -Stiff and hypoxic microenvironments promote the development of breast CSC through modulation of ILK. - Depletion of ILK in ovo significantly abrogated the tumorigenic and metastatic potential of invasive BC cells. |
-ILK signals through the PI3K/Akt to regulate the development of CSCs | |
| [56] | √ | √ | -In vitro (MCF-7, MDA-MB-231, MDA-MB-468, SUM-159) 1) IL-6 treatment 2) shRNA or pharmacological inhibition of ILK -In vivo |
-ILK attenuation blocks estrogen-independent tumor growth | -IL-6 regulates ILK expression via E2F1 and NFkB to activate again IL-6. | |
| [58] | √ | −64 BC samples for real-time PCR -163 BC samples for immunohistochemistry |
High ILK expression was correlated with tumor size, grade, stage, ER status, metastasis, and reduced overall survival. | |||
| [59] | √ | −96 phyllodes BC | -High ILK expression in the tumor and association with increasing tumor grade. | Analysis of EMT-related genes: -decreased E-cadherin and β-catenin -increased expression of N-cadherin, vimentin, Snail, ZEB1 ,and Twist |