Roles of the ING1 Epigenetic Regulator in Breast Cancer
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AbstractING proteins are epigenetic “readers” that can target various chromatin modifying complexes to chromatin. They are involved in various cellular processes such as DNA repair, apoptosis and cellular senescence. This study focuses on examining the potential role of ING1 as a therapeutic agent and prognostic marker for breast cancer. We began by asking whether dysregulating epigenetic pathways with different chemical inhibitors could show synergistic effects with ING1 on killing cancer cells. We tested whether ING1 could synergize better with chemotherapeutics that target the same epigenetic mechanism or a different epigenetic mechanism. Combination treatment of ING1b with LBH589 (HDAC inhibitor) showed synergy, but the combination of ING1b with 5azaC (DNMT inhibitor), thus targeting two distinct epigenetic mechanisms, was more effective. Adenoviral delivery of ING1b combined with 5azaC also inhibited cancer cell growth in a xenograft model and led to tumor regression. These data showed that targeting distinct epigenetic pathways in our model was more effective in blocking cancer cell line growth than targeting the same pathway with multiple agents. Since ING1 expression is frequently repressed in breast carcinomas, but its mechanistic role in breast cancer development and metastasis was unknown, we analyzed ING1 levels in patient samples and correlated it to patient outcome. We also studied the effects of altering ING1 levels in metastasis assays in vitro and mouse metastasis model in vivo. ING1 levels were lower in tumors compared to adjacent normal breast tissue and correlated with tumor size and distant recurrence. ING1 could also predict disease-specific and distant metastasis-free survival in these patients. Decreasing levels of ING1 increased, and increasing levels decreased migration and invasion of MDA-MB231 cells in vitro. ING1 overexpression also blocked cancer cell metastasis in vivo and eliminated tumor-induced mortality in mouse models. Lastly, we determined if ING1 expression could predict breast cancer patient outcome. We found that stromal cell expression of ING1 showed an inverse correlation with patient survival. ING1 also correlated with tumor grade in these patients and multivariate analysis showed that ING1 was an independent prognostic marker in the breast cancer cohort we tested. This study provides important pre-clinical data that could help establish ING1 as a prognostic and therapeutic agent for breast cancer.
CitationThakur, S. (2014). Roles of the ING1 Epigenetic Regulator in Breast Cancer (Unpublished doctoral thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/27691
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