关键词：乳腺癌；磷酸化蛋白；细胞；脱氧核糖核酸
摘 要：PCNA, an essential protein in the DNA synthesis and repair, was shown to be phosphorylated at Y2111 by a nuclear kinase. A consequence of this post-transitional modification has been highly correlated with a reduced survival rate of breast cancer patients. However, no basic of clinical studies have addressed if these inhibitors down-regulate the nuclear function of the protein. The original observations indicated that the EGFR was a major kinase involved in this phosphorylation. Inhibitors of EGFR have exciting potential in treatment but have failed to show clinical efficacy as a mono-therapy treatment option for breast cancer patients. By screening a panel of protein kinase inhibitors in triple negative breast cells for impact on phosphorylation, a direct correlation with EGFR inhibition is not indicated, rather a broader network connecting PCNA modification on chromatin with DNA damage response is implicated. Novel bioconjugates of getfitinib (Iressa) with nuclear targeting peptide-peptoid hybrid sequences have been shown to retain growth inhibitory activity in this context and open avenues for utility in research and new therapies. A new analytical method for enhanced detection of the phosphorylated PCNA isoforms has been shown to be feasible. In addition, by adopting this assay to screen nuclear proteomes of breast tumor cells indicated a more diverse array of PCNA isoforms bearing post-translational modifications opening the door to select specific markers to stage breast cancer patients for molecular therapies.