CKIepsilon as a cause of breast cancer verified in fruit flies.

4. 6. 2011 TOP Stories 533x

(from the laboratory of Tomas Dolezal)

More than 20 years ago, the group of Prof. Peter Bryant (University of California, Irvine) found mutations which caused overgrowth of imaginal discs in Drosophila larvae (imaginal discs give rise to adult appendages). They later identified human genes homologous to the genes carrying those mutations in flies and found that there is remarkably high rate of somatic mutations in one of those genes - Casein Kinase Iε or CKIε (homolog of fly's Disc overgrown or Dco) - in human breast cancer tissues. However functional study was needed to verify if these mutations are actually the cause of cancer since tumor tissues usually contain high numbers of "passenger" mutations. Since human CKIε and Drosophila Dco gnese are very similar - all sequences where mutations were found are conserved - we decided to re-create human mutations in the fly genome to test their effects in vivo.

 

mutant dco[L39Q] and normal larva in electron microscopy

As seen on the picture from electron microscopy, the most frequent human breast cancer mutation L39Q causes striking overgrowth phenotype in Drosophila larvae. For example compared to flat wild-type wing imaginal discs (depicted in green), the dco[L39Q] mutant discs (red) shows incresed growth in all directions. This experiment strongly suggest that the mutations in CKIε are actually the cause of cancer.

 


 

Since we tested the mutations in vivo, we were also able to find out which signaling cascade is affected by these mutations - newly recognized Fat/Warts signaling which is an important regulator of the overall organ size both in humans and flies. This is well demonstrated by comparing the average size od adult wings - the blue wing of double heterozygote in dco[L39Q] and warts mutations is much bigger than the pink wild-type wing. There are numerous recent reports showing that this signaling cascade is often mutated in breast cancer and some other types of cancer.

 

wild-type (pink) and dco[L39Q]/wts (blue) wings

Dolezal T, Kucerova K, Neuhold J, Bryant PJ (2010). Casein kinase I epsilon somatic mutations found in breast cancer cause overgrowth in Drosophila. Int J Dev Biol 54: 1419 – 1424