Abstract

Abstract We recently discovered that TRIM24 is an E3-ubiquitin ligase that targets p53 for degradation in embryonic stem cells and breast cancer cell lines. TRIM24 functions in human cells as a reader of dual histone marks and binds chromatin and estrogen receptor (ER) to activate estrogen-dependent genes associated with cellular proliferation and tumor development. Intriguingly, we and others have shown that over-expression of TRIM24 is associated with poor prognosis and worse survival in breast cancer patients. Whether TRIM24 is causal in malignant transformation of breast epithelial cells during breast tumor development and progression is not known. Furthermore the mechanism that drives deregulated expression of TRIM24 in breast cancer is not understood. To develop a timeline of TRIM24 deregulation during malignant transformation, we used an isogenic human mammary epithelial cell (HMEC) model system that allows for assessment of molecular changes that occur at the earliest stages of multistep human breast carcinogenesis. Our analysis of TRIM24 expression in HMECs transitioning from finite lifespan, to immortality and to malignantly transformed HMECs showed gradual up-regulation of TRIM24 at both RNA and protein levels early in the transformation process. Consistent with these findings, Immunohistochemical (IHC) staining of TRIM24 in clinical breast tumor samples from a breast cancer progression array showed increased TRIM24 expression in hyperplasia, ductal carcinoma in situ (DCIS) and invasive carcinoma, compared to normal breast tissues. To understand the mechanism of TRIM24 deregulation in breast tumor progression, we studied the TRIM24 promoter region for aberrant DNA methylation changes by bisulfite genomic sequencing. There were no aberrant DNA methylation changes in HMEC transitioning from finite lifespan to malignant transformation suggesting that TRIM24 gene expression is regulated by mechanisms other than DNA methylation. Interestingly, Chromatin Immunoprecipitation (ChIP) studies in finite lifespan HMECs at the TRIM24 promoter showed an enrichment of repressive histone marks H3K9me2 and H3K9me3 which gradually decreased in immortal and malignantly transformed mammary epithelial cells. Further studies to see if TRIM24 is involved in transformation of normal mammary epithelial cells by stably overexpressing TRIM24 in HMECs are currently ongoing. Also more studies are ongoing to define additional levels of regulation of TRIM24, and which transcription factors are involved in its deregulated expression in breast cancer. Our studies suggest a unique role of TRIM24 in early steps of mammary carcinogenesis. Therefore, our study may provide valuable insights into the rational development of TRIM24-targeted therapeutic strategies against breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2213. doi:1538-7445.AM2012-2213

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