Remarkably, tumors defective for both ATM and p53 were more selleck compound prone to drug Inhibitors,Modulators,Libraries induced cell killing and tumors with functional ATM but non functional p53 could be sensitized by pharmacologic suppression of ATM signaling. Similar results have been reported for other TSGs involved in controlling genomic stability, such as the inhibition of PARP 1 in BRCA1 2 deficient breast and ovarian tumors which selectively kills the cancer cells while sparing normal cells with a functional repair path way. Together, these findings highlight the impor tance for a detailed knowledge of genetic defects in tumors to identify those patients who will most likely respond to specific genotoxic drugs. To date, defined Fbxw7 hCdc4 substrates are nuclear proteins degraded by the Fbxw7 hCdc4 a and or Fbxw7 hCdc4 g isoforms, whereas Fbxw7 hCdc4 b specific substrates still await discovery.

Fbxw7 hCdc4 b localizes to the cytoplasm Inhibitors,Modulators,Libraries and could potentially target a pro apoptotic substrate or a protein involved in DNA damage signaling that when stabilized sensitize tumor cells to chemotherapeu tic drugs. Interestingly, Mao et al. recently reported that Fbxw7 hCdc4 Inhibitors,Modulators,Libraries targets the mammalian target of rapamy cin for degradation. The Fbxw7 hCdc4 iso form responsible for mTor degradation was not defined in this study, but its noteworthy that mTor localizes to the cytosol and that breast cancer cells with loss of Fbxw7 hCdc4 were shown to be more sensitive to mTor inhibitors. We have just begun to understand the complex inter play between FBXW7 hCDC4, its target oncoproteins and other critical cancer genes.

Inhibitors,Modulators,Libraries For example, p53 is a direct transcriptional regulator of FBXW7 Inhibitors,Modulators,Libraries hCDC4 expression. However, the functional relationship between these TSGs is still unclear and FBXW7 hCDC4 has also been suggested to act upstream of p53. Furthermore, a differential relationship with the various FBXW7 hCDC4 isoforms is possible. A recent study in gastric cancer revealed that patient samples with p53 mutations had lower FBXW7 hCDC4 a mRNA levels and those patients also had a poor prognosis compared with the other subgroups. In line with these data, in our analysis of breast cancer specimens, we also found selleck chemicals Ganetespib a statistically significant correlation between low FBXW7 hCDC4 a expression and p53 mutation. To exclude the possibility that downregulation of FBXW7 hCDC4 a expression is due to promoter methylation, we have analysed the FBXW7 hCDC4 a CpG island for methylation. Methylation was not observed in any of the primary breast tumor specimens analysed, independently of FBXW7 hCDC4 a mRNA levels, indicating that p53 mutational status is major decisive factor in the regulation of FBXW7 hCDC4 a expression in breast cancer.