Abstract
The integrin linked kinase (ILK) is a cytoplasmic effector of integrin receptors, involved in the regulation of integrin binding properties as well as the activation of cell survival and proliferative pathways, including those involving MAP kinase, PKB/Akt and GSK-3beta. Overexpression of ILK in cultured intestinal and mammary epithelial cells has been previously shown to induce changes characteristic of oncogenic transformation, including anchorage-independent growth, invasiveness, suppression of anoikis and tumorigenicity in nude mice. In order to determine if ILK overexpression can result in the formation of mammary tumors in vivo, we generated transgenic mice expressing ILK in the mammary epithelium, under the transcriptional control of the mouse mammary tumor virus (MMTV) long terminal repeat (LTR). By the age of 6 months, female MMTV/ILK mice developed a hyperplastic mammary phenotype, which was accompanied by the constitutive phosphorylation of PKB/Akt, GSK-3beta and MAP kinase. Focal mammary tumors subsequently appeared in 34% of the animals at an average age of 18 months. Given the focal nature and long latency of the tumors, however, additional genetic events are likely required for tumor induction in the MMTV/ILK mice. These results provide the first direct demonstration of a potential oncogenic role for ILK, which is upregulated in human tumors and tumor cell lines.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenocarcinoma, Papillary / enzymology
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Adenocarcinoma, Papillary / genetics
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Animals
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Breast / metabolism
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Breast / pathology*
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Transformation, Neoplastic / genetics
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Enzyme Induction
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Epithelial Cells / metabolism
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Female
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Gene Expression Regulation
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Glycogen Synthase Kinase 3
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Humans
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Hyperplasia
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Integrins / metabolism
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MAP Kinase Signaling System
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Mammary Neoplasms, Experimental / enzymology*
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Mammary Neoplasms, Experimental / genetics
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Mammary Tumor Virus, Mouse / genetics
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Metaplasia
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Mice
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Mice, Transgenic
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Organ Specificity
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Phosphorylation
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Recombinant Fusion Proteins / physiology
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Terminal Repeat Sequences / genetics
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Transgenes
Substances
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Integrins
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Neoplasm Proteins
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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integrin-linked kinase
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3