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Gene expression profiles of human breast cancer cell lines

ABSTRACT: Numerous epithelial-to-mesenchymal transition (EMT)-promoting transcription factors have been implicated in tumorigenesis or metastasis, as well as chemoresistance of cancer. However, the underlying mechanism mediating these processes is unclear. Here we report that Foxq1, a forkhead box-containing transcription factor and EMT-inducing gene, promotes stemness traits and chemoresistance in mammary epithelial cells. We identify Twist1, Zeb2, and PDGFRα and β as Foxq1 downstream targets using an expression profiling assay. Further studies reveal that PDGFRα and β can be directly regulated by Foxq1, or indirectly through Twist1. Knockdown of both PDGFRα and β shows more significant effects on reversing Foxq1-promoted oncogenesis in vitro and in vivo than knockdown by either PDGFRα or β alone. PDGFRβ, but not PDGFRα, shows potent effects in reversing Foxq1-promoted stemness traits. Moreover, pharmacological inhibition or gene silencing of PDGFRs sensitize mammary epithelial cells to chemotherapeutic agents in vitro and in vivo. These findings collectively indicate PDGFRs as critical mediators underlying breast cancer tumorigenesis and chemoresistance driven by EMT promoting genes, which have potential clinical implications for cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE46834 | GEO | 2013/05/11

SECONDARY ACCESSION(S): PRJNA202442

REPOSITORIES: GEO

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Project description:Purpose: to characterize epigenetic changes following Twist1 mediated Epithelial-Mesenchymal Transition in human Methods: we characterized the epigenetic and transcriptome landscapes using whole genome transcriptome analysis by RNA-seq, DNA methylation by digital restriction enzyme analysis of methylation (DREAM) and histone modifications by CHIP-seq of H3K4me3 and H3K27me3 in immortalized human mammary epithelial cells relative to cells induced to undergo EMT by Twist1. Results: EMT is accompanied by focal hypermethylation and widespread global DNA hypomethylation, predominantly within transcriptionally repressed gene bodies. At the chromatin level, the number of gene promoters marked by H3K4me3 increases by more than one fifth; H3K27me3 undergoes dynamic genomic redistribution characterized by loss at half of gene promoters and overall reduction of peak size by almost one-half. This is paralleled by increased phosphorylation of EZH2 at serine 21. Among genes with highly altered mRNA expression, 23.1% switch between H3K4me3 and H3K27me3 marks, and those point to the master EMT targets and regulators CDH1, PDGFRA and ESRP1. Strikingly, Twist1 increases the number of bivalent genes by more than two fold. Inhibition of the H3K27 methyltransferases EZH2 and EZH1, which form part of the PRC2 complex, results in blocking EMT and stemness properties. Conclusion: Our findings demonstrate that the EMT program requires epigenetic remodeling by the Polycomb/Trithorax complexes leading to increased cellular plasticity which suggests that its inhibition will prevent EMT, and the associated breast cancer metastasis. DREAM profiles of human mammary epithelial cells before (HMLE_parental) and after Twist1 transfection (HMLE_Twist) were generated in monolayer (HMLE_Twist2D) and sphere culture by deep sequencing using Illumina GAIIx or Illumina hiseq2000. Furthermore, DREAM profile was also obtained in parental human mammary epithelial cells transfected with GFP