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Isolation of Breast Tumor Suppressor Genes from Chromosome 11p

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Final rept. 23 Aug 1996-23 Aug 2001

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In published studies, we have shown that chromosome 11p15.5 exhibits loss of heterozygosity LOH in 60 of breast tumors, and that there is a significant correlation between lip LOH, lymphatic invasion and aggressive metastatic disease. Our data suggests that chromosome 11p15.5 harbors a tumormetastasis suppressor gene. An intriguing candidate gene that we have mapped to the tumormetastasis suppressor locus on chromosome 11p15.5 is Integrin-linked Kinase ILK. ILK is a newly identified ankyrin-repeat containing serinethreonine kinase that binds to the cytoplasmic domains of both 81 and the 83 integrins. Here, we present evidence that the Integrin-Linked Kinase ILK gene maps to the commonly deleted chromosome 11p15.5 and suppresses malignant growth of human breast cancer cells both in vitro and in vivo. ILK is expressed in normal breast tissue but-not in metastatic breast cancer cell lines or in advanced breast cancers. Transfection of wild-type ILK into the MDA-MBA35 mammary carcinoma cells potently suppressed their growth and invasiveness in vitro, and reduced the cells ability to induce tumors and metastasize in athymic mice. Conversely, expression of the ankyrin repeat or catalytic domain mutants of ILK failed to suppress the growth of these cells. Growth suppression by ILK is not due to apoptosis but is mediated by its ability to block cell cycle progression in the G1 phase. These findings directly demonstrate that ILK deficiency facilitates neoplastic growth and suggest a novel role for the ILK gene in tumor suppression.

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  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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