Abstract
Cancer specific mutations of the p53 tumor suppressor gene are the most prevalent genetic lesions that underpin breast cancer pathogenesis and progression. In most cases, mutations result in a single amino acid substitution in the DNA-binding domain of p53. Such missense mutant forms of p53 accumulate at high levels in tumor cells. Recent advances demonstrated that missense p53 mutants have a critical role in driving cancer metastasis. Thus elimination of mutant p53 can potentially prevent metastatic progression of breast cancer. Inhibitors of histone deacetylases (HDACi) have proven anticancer effects and vorinostat, an FDA approved HDACi, has been in clinical use for treating certain malignancies. HDACi shapes epigenetic landscapes by restoring histone acetylation that is often suppressed in breast and other cancer types. One consequence of the restoration of histone acetylation is reactivation of tumor suppressors and other genes. Other effects of HDACi include modulation of posttranslational acetylation of non-histone proteins, which can influence their biochemical functions, resulting in a net effect of enhanced cell cycle arrest and apoptosis. Interestingly, HDACi profoundly suppresses the expression levels of p53. We found that this suppression occurs irrespectively of the mutational status of p53, but surprisingly only in certain types of cancer cells such as breast cancer. We further showed that the expression of exogenous p53 under a heterologous promoter was not affected by HDACi. These results suggest that HDACi might downregulate p53 through gene repression. To further test this idea, we assessed the effects of HDACi treatment and ectopic expression of classical HDACs (Classes I, II and IV) on luciferase reporter gene under the control of the p53 promoter. Among the 11 classical HDACs, ectopic expression of HDAC7 and HDAC10 seem to upregulate the reporter gene. We are currently investigating how these HDACs interact with the p53 promoter and what transcription factors and corepressors are involved in regulating p53 expression. Additionally, we are studying roles of depleting mutant forms of p53 by HDACi in suppressing migration, invasion and metastasis of breast cancer cells and assessing the efficacy of HDACi in conjunction with p53 gene therapy for treating breast cancer in a mouse model. (This work was supported by Bankhead-Coley Cancer Research Program of the Florida Department of Health, Stop! Children's Cancer, Inc. and the NIH.)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4517.
- ©2010 American Association for Cancer Research
Volume 70, Issue 8 Supplement
