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Re-engineered p53 activates apoptosis in vivo and causes primary tumor regression in a dominant negative breast cancer xenograft model

Abstract

Inactivation of p53 pathway is reported in more than half of all human tumors and can be correlated to malignant development. Missense mutation in the DNA binding region of p53 is the most common mechanism of p53 inactivation in cancer cells. The resulting tumor-derived p53 variants, similar to wild-type (wt) p53, retain their ability to oligomerize via the tetramerization domain. Upon hetero-oligomerization, mutant p53 enforces a dominant negative effect over active wt-p53 in cancer cells. To overcome this barrier, we have previously designed a chimeric superactive p53 (p53-CC) with an alternative oligomerization domain capable of escaping transdominant inhibition by mutant p53 in vitro. In this report, we demonstrate the superior tumor suppressor activity of p53-CC and its ability to cause tumor regression of the MDA-MB-468 aggressive p53-dominant negative breast cancer tumor model in vivo. In addition, we illustrate the profound effects of the dominant negative effect of endogenous mutant p53 over wt-p53 in cancer cells. Finally, we investigate the underlying differential mechanisms of activity for p53-CC and wt-p53 delivered using viral-mediated gene therapy approach in the MDA-MB-468 tumor model.

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Acknowledgements

We acknowledge the use of DNA/Peptide Core and Flow Cytometry Core (NCI Cancer Center Support Grant P30 CA042014, Huntsman Cancer Institute). Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number R01-CA151847. We also acknowledge support of funds in conjunction with grant P30 CA042014 awarded to Huntsman Cancer Institute. We thank Sheryl Tripp (ARUP Laboratories), Ben Bruno and Geoff Miller for scientific discussions.

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Okal, A., Matissek, K., Matissek, S. et al. Re-engineered p53 activates apoptosis in vivo and causes primary tumor regression in a dominant negative breast cancer xenograft model. Gene Ther 21, 903–912 (2014). https://doi.org/10.1038/gt.2014.70

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