Abstract
Abstract
Cell cycle regulation and DNA repair following damage are essential for maintaining genome integrity which further leads to oncogenesis. DNA damage activates checkpoints in order to repair damaged DNA prior to exit to the next phase of cell cycle. Recently, we have shown the role of Ada3, a component of various histone acetyltransferase complexes, in cell cycle regulation, as loss of Ada3 results in mouse embryonic lethality. Furthermore cre-mediated deletion of Ada3 in Ada3fl/ fl mouse embryonic fibroblasts (MEFs), led to enhanced chromosomal aberrations, which further increased upon DNA damage Significantly, Ada3 loss was associated with increased levels of phospho-ATM ), γH2AX, 53BP1 andRAD51 although radiation response was intact in Ada3-/- cells. Notably, Ada3-/- cells exhibited a significant delay in disappearance of DNA damage foci for several critical proteins involved in the DNA repair process. Given the frequent dysregulation of cell cycle regulatory components in human cancer, we used immunohistochemistry of paraffin embedded tissues to examine Ada3 expression in breast cancer tissue. These analyses showed predominant nuclear Ada3 staining correlated with ER+ status,whereas predominant cytoplasmic Ada3 staining negatively correlated with ER+ status, but positively correlated with ErbB2, EGFR, and Ki67. Furthermore, a positive correlation of cytoplasmic Ada3 was observed with higher histological grade, mitotic counts, Nottingham Prognostic Index, and positive vascular invasion. Patients with nuclear Ada3 and ER positivity have better breast cancer specific survival and distant metastasis free survival. Significantly, cytoplasmic expression of Ada3 showed a strong positive association with reduced BCSS and DMFS in ErbB2+/EGFR+ patients. These results show nuclearAda3 staining in breast cancer tissues correlates with ER+ expression and together serve as a marker of good prognosis, whereas predominant cytoplasmic Ada3 expression correlates with ErbB2+/EGFR+ expression and together is a marker of poor prognosis.
Our current efforts are focused on dissecting out the molecular pathways for cytoplasmic Ada3. The hypothesis that we are testing are i) Is there a role of second isoform of Ada3 that is predominantly cytoplasmic or ii) posttranslational modification (such as phosphorylation, acetylation or ubiquitination) of Ada3 regulates cytoplasmic expression of Ada3.
Citation Format: Sameer Mirza, Shakur Mohibi, Bryan J. Katafiasz, Jun Wang, Bhavana J. Dave, Emad A. Rakha, Alaa Alshareeda, Hamid Band, Vimla Band. Ada3, a component of ATAC complex is involved in regulation of the Genomic stability, DNA repair process and breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B120.