Browsing by Author "Jeong, Jaesik"

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    An empirical Bayes model for gene expression and methylation profiles in antiestrogen resistant breast cancer
    (BMC, 2010-11-25) Jeong, Jaesik; Li, Lang; Liu, Yunlong; Nephew, Kenneth P.; Huang, Tim Hui-Ming; Shen, Changyu; Biostatistics, School of Public Health
    Background The nuclear transcription factor estrogen receptor alpha (ER-alpha) is the target of several antiestrogen therapeutic agents for breast cancer. However, many ER-alpha positive patients do not respond to these treatments from the beginning, or stop responding after being treated for a period of time. Because of the association of gene transcription alteration and drug resistance and the emerging evidence on the role of DNA methylation on transcription regulation, understanding of these relationships can facilitate development of approaches to re-sensitize breast cancer cells to treatment by restoring DNA methylation patterns. Methods We constructed a hierarchical empirical Bayes model to investigate the simultaneous change of gene expression and promoter DNA methylation profiles among wild type (WT) and OHT/ICI resistant MCF7 breast cancer cell lines. Results We found that compared with the WT cell lines, almost all of the genes in OHT or ICI resistant cell lines either do not show methylation change or hypomethylated. Moreover, the correlations between gene expression and methylation are quite heterogeneous across genes, suggesting the involvement of other factors in regulating transcription. Analysis of our results in combination with H3K4me2 data on OHT resistant cell lines suggests a clear interplay between DNA methylation and H3K4me2 in the regulation of gene expression. For hypomethylated genes with alteration of gene expression, most (~80%) are up-regulated, consistent with current view on the relationship between promoter methylation and gene expression. Conclusions We developed an empirical Bayes model to study the association between DNA methylation in the promoter region and gene expression. Our approach generates both global (across all genes) and local (individual gene) views of the interplay. It provides important insight on future effort to develop therapeutic agent to re-sensitize breast cancer cells to treatment.
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    An inhibitor of the mitotic kinase, MPS1, is selective towards pancreatic cancer cells
    (Office of the Vice Chancellor for Research, 2014-04-11) Bansal, Ruchi; Blackburn, Corrine; Brown, Lyndsey; Gasaway, Rachel; Victorino, Jose; Jeong, Jaesik; Gore, Jesse; March, Keith L.; Herbert, Brittney-Shea; Colombo, Riccardo; Korc, Murray; Slee, Roger B.; Grimes, Brenda R.
    The abysmal five year pancreatic cancer survival rate of less than 6% highlights the need for new treatments for this deadly malignancy. Cytotoxic drugs normally target rapidly dividing cancer cells but unfortunately often target stem cells resulting in toxicity. This warrants the development of compounds that selectively target tumor cells. An inhibitor of the mitotic kinase, MPS1, which has been shown to be more selective towards cancer cells than non-tumorigenic cells, shows promise but its effects on stem cells has not been investigated. MPS1 is an essential component of the Spindle Assembly Checkpoint and is proposed to be up-regulated in cancer cells to maintain chromosomal segregation errors within survivable limits. Inhibition of MPS1 kinase causes cancer cell death accompanied by massive aneuploidy. Our studies demonstrate that human adipose stem cells (ASCs) and can tolerate higher levels of a small molecule MPS1 inhibitor than pancreatic cancer cells. In contrast to PANC-1 cancer cells, ASCs and telomerase-immortalized pancreatic ductal epithelial cells did not exhibit elevated chromosome mis-segregation after treatment with the MPS1 inhibitor for 72hrs. In contrast, PANC-1 pancreatic cancer cells exhibited a large increase in chromosomal mis-segregation under similar conditions. Furthermore, growth of ASCs was minimally affected post treatment whereas PANC-1 cells were severely growth impaired suggesting a favorable therapeutic index. Our studies, demonstrate that MPS1 inhibition is selective towards pancreatic cancer cells and that stem cells are less affected in vitro. These data suggest MPS1 inhibition should be further investigated as a new treatment approach in pancreatic cancer.
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    Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715
    (American Association for Cancer Research, 2014-02) Slee, Roger B.; Grimes, Brenda R.; Bansal, Ruchi; Gore, Jesse; Blackburn, Corinne; Brown, Lyndsey; Gasaway, Rachel; Jeong, Jaesik; Victorino, Jose; March, Keith L.; Colombo, Riccardo; Herbert, Brittney-Shea; Korc, Murray; Department of Medical and Molecular Genetics, IU School of Medicine
    Most solid tumors, including pancreatic ductal adenocarcinoma (PDAC), exhibit structural and numerical chromosome instability (CIN). Although often implicated as a driver of tumor progression and drug resistance, CIN also reduces cell fitness and poses a vulnerability that can be exploited therapeutically. The spindle assembly checkpoint (SAC) ensures correct chromosome-microtubule attachment, thereby minimizing chromosome segregation errors. Many tumors exhibit upregulation of SAC components such as MPS1, which may help contain CIN within survivable limits. Prior studies showed that MPS1 inhibition with the small molecule NMS-P715 limits tumor growth in xenograft models. In cancer cell lines, NMS-P715 causes cell death associated with impaired SAC function and increased chromosome missegregation. Although normal cells appeared more resistant, effects on stem cells, which are the dose-limiting toxicity of most chemotherapeutics, were not examined. Elevated expression of 70 genes (CIN70), including MPS1, provides a surrogate measure of CIN and predicts poor patient survival in multiple tumor types. Our new findings show that the degree of CIN70 upregulation varies considerably among PDAC tumors, with higher CIN70 gene expression predictive of poor outcome. We identified a 25 gene subset (PDAC CIN25) whose overexpression was most strongly correlated with poor survival and included MPS1. In vitro, growth of human and murine PDAC cells is inhibited by NMS-P715 treatment, whereas adipose-derived human mesenchymal stem cells are relatively resistant and maintain chromosome stability upon exposure to NMS-P715. These studies suggest that NMS-P715 could have a favorable therapeutic index and warrant further investigation of MPS1 inhibition as a new PDAC treatment strategy.