The focal adhesion protein Integrin-Linked Kinase (ILK) as an important player in breast cancer pathogenesis

Figures & data

Figure 1. Diagram depicting the main molecular interactions of ILK at FAs as well as the major signaling pathways involved.

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 (LCC6^Her2, MCF7^Her2, 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, LCC6^Her2, 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

Figure 2. Diagram summarizing the role of ILK in relation to basic cancer properties in BC. The signaling molecules involved are also indicated.

Figure 3. Summary of the studies performed in vitro, in vivo or in human BC samples regarding the role of ILK in BC using different experimental approaches.

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