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RNA-seq to profile the transcriptome changes induced by the EZH2 degrader MS1943

ABSTRACT: To gain mechanistic insights into how MS1943 induces cell death, MDA-MB-468 cells were treated with 5 µM of MS1943 or DMSO control and changes of gene expression were assessed after 3 days of treatment. Interestingly, MS1943-treated cells were characterized by a unique set of deregulated genes that could readily separate them from control cells. We identified 8,730 significant differentially expressed genes with a false discovery rate (FDR) at 5%, in which 2,120 genes have an absolute log fold change above 1. We next performed gene set enrichment analyses (GSEA) that capture pathways perturbed towards both directions simultaneously using the 24,448 ranked genes identified in our dataset and annotated in ENSEMBL (version 94) against the KEGG pathways and the hallmarks gene set collection (MSigDB V6.2). Induction of the unfolded protein response (UPR) / endoplasmic reticulum (ER)-stress pathway was commonly identified using both types of analyses and we therefore decided to pursue this further.

ORGANISM(S): Homo sapiens

PROVIDER: GSE130503 | GEO | 2019/11/17

REPOSITORIES: GEO

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Project description:Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in multiple intracellular signaling pathways promoting tumor growth. mTOR is aberrantly activated in a significant portion of breast cancers and is a promising target for treatment. Rapamycin and its analogues are in clinical trials for breast cancer treatment. Patterns of gene expression (metagenes) may also be used to simulate a biologic process of effects of a drug treatment. In this study, we tested the hypothesis that the gene-expression signature regulated by rapamycin could predict disease outcome for patients with breast cancer. Results: Colony formation and sulforhodamine B (IC50 < 1nM) assays, and xenograft animals showed that MDA-MB-468 cells were sensitive to treatment with rapamycin. The comparison of in vitro and in vivo gene expression data identified a signature, termed rapamycin metagene index (RMI), of 31 genes upregulated by rapamycin treatment in vitro as well as in vivo (false discovery rate of 10%). In the Miller dataset, RMI was significantly associated with tumor size or lymph node status. High (>75) percentile) RMI was significantly associated with longer survival (P = 0.015). On multivariate analysis, RMI (P = 0.029), tumor size (P = 0.015) and lymph node status (P = 0.01) were prognostic. In van 't Veer study, RMI was not associated with the time to develop distant metastasis (P = 0.41). In Wang dataset, RMI predicted time to disease relapse (P = 0.09). Conclusions: Rapamycin-regulated gene expression signature predicts clinical outcome in breast cancer. This supports the central role of mTOR signaling in breast cancer biology and provides further impetus to pursue mTOR-targeted therapies for breast cancer treatment. Mol Cancer. 2009 Sep 24;8(1):75. Experiment Overall Design: Rapamycin treatment of MDA-MB-468 breast cancer cell line: Experiment Overall Design: MDA-MB-468 cell line was treated by DMSO (vehicle) and 100 nM rapamycin for 24 hours. We sought to identify differentially expressed genes. Experiment Overall Design: Rapamycin treatment of breast tumor xenografts: Experiment Overall Design: MDA-MB-468 cells were inoculated in the mammary fat pad of female nude mice. When resulting tumor volumes had reached 75-150 mm3, the mice were divided in four groups. Groups 1 and 2 received a single injection of DMSO (vehicle) or rapamycin (15 mg/kg) intraperitoneally and sacrificied 24 h later (1-day groups). Groups 3 and 4 received weekly injections of DMSO or rapamycin for 3 weeks and sacrificied 24 h after the last injection (22-day groups).

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RNA-seq to profile the transcriptome changes induced by the EZH2 degrader MS1943

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