Gu Xiao

Detection and Targeting of Triple Negative Breast Cancer with a Nuclear Directed p53 Tetramerization Domain Peptide

Gu Xiao, George Annor, Kimberly Fung, Brian Zeglis and Jill Bargonetti

Triple negative breast cancer (TNBC) is more prevalent in African Americans (AAs) and TNBC in AA has been associated with worst overall survival. p53 is mutated in approximately 80% of patients in TNBC. A major challenge of targeting mutant p53  (mtp53) has been how to detect and block the protein in vivo. The high stability of mtp53 in cancer patients suggests new strategies for targeting the protein for diagnostics and therapy (theranostics). We generated a novel peptide (Cy5p53Tet) that contains the p53 tetramerization domain conjugated to a fluoroprobe for tumor imaging and inhibiting of the gain of function of mtp53. We demonstrated by live cell imaging and flow cytometry the higher uptake of Cy5p53Tet peptide for binding to mtp53 in the TNBC cell line MDA-MB- 468 than with wild type p53 in the Estrogen Receptor positive breast cancer cell line MCF-7. In addition, Cy5p53Tet signal reduction was found when mtp53 was depleted. In vivo analysis in mice bearing MDA-MB-468 xenografts showed that 12 minutes post injection, the Cy5p53tet peptide was able to detect tumors. The specificity of this peptide was confirmed in mice with a higher uptake of the Cy5p53tet peptide in MDA-MB-468 xenografts compared to in MCF7 xenografts. In vitro co-precipitation and cross-link assays validated Cy5p53tet peptide binding to tetrameric mtp53. In addition, higher nuclear Cy5p53tet peptide staining was observed in mtp53 TNBC than in normal mammary epithelial cell lines. Selective detecting by Cy5p53Tet peptide suggests the importance of targeting towards TNBC in multi-ethnic populations.

Email questions and comments about this abstract to xiao@genectr.hunter.cuny.edu.