Three-pronged approach identifies new cancer target

By Dr Matt Wilkinson

- Last updated on GMT

Related tags: Cancer cells, Cancer

US researchers have developed a three part screening process to
find new cancer genes and used it to identify a new gene associated
with about a third of all breast cancers.

This latest research, published in the current issue of the Cell​, used a combination of techniques to link the over-expression of the gene IKBKE (inducible kappa beta-kinase) with the onset of breast cancer. A major problem in the identification of genes that are associated with any disorder is the large genetic variation between individuals and the vast amount of data that is acquired. By using the three-part screening process the researchers were able to tighten the net around the key oncgene while dismissing the 'background noise' caused by related genes. "Current technologies - particularly 'microarray' sensors, which read the activity and changes in thousands of genes at a time - enable us to locate dozens or even hundreds of gene abnormalities in cancer cells,"​ said co-senior author, Dr William Hahn, of the Dana-Farber Cancer Institute. The large number of genetic abnormalities arises due to the 'genetic disarray' observed in many cancer cells which complicates the hunt for key genes. "The challenge is to winnow this group to find the genes most centrally involved in cancer initiation and maintenance,"​ he continued. The researchers started off by creating a library of 354 human kinases which were injected into normal epithelial cells to see if they mimicked the ability of PI3K (phosphoinosotide-3 kinase) to transform the normal cells into cancer cells - five of them did. They then used a variety of genome-scale approaches, including SNP (single nucleotide polymorphism) and aCGH (array comparative genome hybridisation) high density microarrays to determine if genes for any of the five identified kinases were unusually abundant in cancer cells. Significant overexpression was found of 1q32 involving the IKBKE gene but not the other genes. Many cancer cells are unusually dependant on oncogenes for their continued viability and the researchers investigated this 'oncogene addiction' by using RNA interference (RNAi) to switch off the gene. This led to a decrease in the cell proliferation and viability of cancerous cells in a number of cell lines. They then explored whether breast cancer cells depend on IKBKE for survival by using RNAi (RNA interference) techniques to switch off the gene, which they did. "This triple screening approach enabled us to study what happened to cells when IKBKE was turned on and when it was shut off, and to take a global look at the genetic alterations within breast cancer cell lines and tumors,"​ said Hahn. "Each method helped 'filter' the information from the previous one, enabling us to zero in on the strongest candidate."

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