Centrosome hyperamplification in human cancer: chromosome instability induced by p53 mutation and/or Mdm2 overexpression

We have previously reported that loss of p53 tumor suppressor protein resul ts in centrosome hyperamplification, which leads to aberrant mitosis and ch romosome instability, Since p53 is either deleted or mutated in human cance rs at a high frequency, we investigated whether human cancers showed centro some hyperamplification, Screening of advanced stage breast ductal carcinom as and squamous cell carcinomas of the head and neck (SCCHN) revealed that centrosome hyperamplification is frequent in both tumor types, Moreover, th rough the analyses of p53 in SCCHN samples by direct sequencing and by loss -of-heterozygosity test, we found that p53 mutations correlated with occurr ence of centrosome hyperamplification. However, in some cases, me observed centrosome hyperamplification in tumors that retained wild-type p53, These tumors contained high levels of Mdm2, Since Mdm2 can inactivate p53 through physical association, we investigated whether Mdm2 overexpression induced centrosome hyperamplification, We found that Mdm2 overexpression, like loss of p53, induced centrosome hyperamplification and chromosome instability i n cultured cells.