Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin‐linked kinase

Abstract

Allelic loss at the short arm of chromosome 11 is one of the most common and potent events in the progression and metastasis of breast cancer. Here, we present evidence that the Integrin-Linked Kinase (ILK) gene maps to the commonly deleted chromosome 11p15. Genetic alterations that occur in breast cancer are believed to be of importance for initiation as well as progression of the disease. These genetic alterations lead to the loss or activation of a number of critical genes, such as those involved in cell proliferation, differentiation, apoptosis and genetic stability. The genetic abnormalities most frequently observed in breast tumors are amplification of proto-oncogenes (MYC, ERBB2 and CCND1), mutations of TP53 and loss of heterozygosity (LOH) on chromosomes 3p, 6q, 7q, 8p, 9p, 11, 13q, 17, 18q and 22q. 1,2 Metastatic phenotypes have been linked to such genes as NME1 (17q), CDH1 (16q), BRMS1 (11q) and KISS1 (1q). 1,3-5 LOH analyses have defined regions of deletion associated with metastasis on chromosomes 3p21, 15q14, 16q22 and 11p15. 2,6 Frequent genetic alterations on chromosome 11p15 suggest a crucial role for this region in breast 6,7 and other adult 8 -12 and childhood cancers. [13][14][15][16][17] More recently, we have mapped 2 distinct regions on chromosome 11p15.5 that are subject to LOH during breast tumor progression and metastasis. 6 LOH at region 1 correlated with tumors that contain ductal carcinoma in situ, suggesting that the loss of a critical gene in this region may be responsible for early events in malignancy. LOH at region 2 correlated with a more aggressive tumor and an ominous outlook for the patient, such as aneuploidy, high S-phase fraction and the presence of metastasis in regional lymph nodes. Although considerable advances have been made in the fine-mapping of chromosome 11p15.5, the tumor/metastasis suppressor gene(s) encoded by this region has evaded identification.Integrin-linked kinase (ILK) is an intriguing serine/threonine kinase that has been implicated in integrin-, growth-factor-and Wnt-signaling pathways. 18 It binds to the cytoplasmic domains of ␤1 and ␤3 integrins and mediates the downstream signaling events in integrin function. 19 Interactions between integrins and their ligands are involved in the regulation of many cellular functions, including embryonic development, cell proliferation, tumor growth and the ability to metastasize. 20 In Drosophila, the absence of ILK function causes defects similar to loss of integrin adhesion, and ILK mutations cause embryonic lethality and defects in muscle attachment. 21 Although ILK maps to the commonly deleted chromosome 11p, the potential of this gene in tumor/metastasis suppression has not been evaluated. We have therefore analyzed the effect of ILK expression on the in vitro and in vivo tumor growth and invasion of human mammary carcinoma cells. MATERIAL AND METHODS Mapping of ILK to LOH region 2Two YAC clones (847a12 and 696H10), a BAC clone (BAC 1760) and a PAC clone (PAC1331) overlapped the LOH region 2 and were used to...

JNK1 determines the oncogenic or tumor-suppressive activity of the integrin-linked kinase in human rhabdomyosarcoma

“…Previous studies have suggested that a region of LOH lies over the ILK locus in numerous cell types, including ERMS, breast carcinoma, and non-small cell lung carcinoma (4). Similarly, ILK functions as a tumor suppressor in MDA-MB-435 breast carcinoma cells, which display LOH at this locus (17). We have extended these results to suggest that ILK functions as a growth suppressor in one putative progenitor cell population for RMS tumors.…”

“…Similarly, ILK expression correlates in many tumor and normal tissues with areas of increased differentiation (13) and can cooperate with ionizing radiation to induce apoptosis in some cancer cells (14)(15)(16). Finally, overexpression of wild-type, but not mutant, ILK could limit tumor formation in MDA-MB-435 xenografts (17), although the mechanism for this finding was not reported.…”

Integrin-linked kinase activity is associated with interleukin-1α-induced progressive behavior of pancreatic cancer and poor patient survival

“…ILK is reported to regulate integrin-mediated cell adhesion and invasion, E-cadherin expression and ECM assembly (Delcommenne et al, 1998;Chen et al, 2004;Edwards et al, 2005;Filipenko et al, 2005). ILK activation is regulated in a phosphatidylinositol 3-kinase (PI3-K)-dependent manner by adhesion to ECM and by growth factors and cytokines (Hannigan et al, 2005;Larue and Bellacosa, 2005).…”

The oncogenic and growth-suppressive functions of the integrin-linked kinase are distinguished by JNK1 expression in human cancer cells

“…[9][10][11] In addition, elevated ILK expression is found in more differentiated regions of solid tumors, 12 and ILK overexpression induces differentiation of L6 rat myoblasts 13 and suppresses MDA-MB-435 breast carcinoma xenograft growth. 14 Further, ILK overexpression synergizes with ionizing radiation to induce apoptosis in A549 non-small cell lung carcinoma (NSCLC), HL60 acute promyelocytic leukemia and Jurkat T cells. 15,16 While these studies indicate a potential growth-suppressive role for ILK in different cellular contexts, limited mechanistic insight has been uncovered.…”