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Genome-wide analysis of gene expression by IFNβ in Transformed HMEC (Epithelial/non-CSC, Mesenchymal/CSC)

ABSTRACT: Triple Negative Breast Cancer (TNBC), the deadliest form of this disease, lacks a targeted therapy. TNBC tumors that fail to respond to chemotherapy are characterized by a repressed Interferon/Signal Transducer and Activator of Transcription (IFN/STAT) gene signature and are often enriched for Cancer Stem Cells (CSCs). We have found that human mammary epithelial cells that undergo an Epithelial-to-Mesenchymal Transition (EMT) following transformation acquire CSC properties. These mesenchymal/CSCs have a significantly repressed IFN/STAT gene expression signature and an enhanced ability to migrate and form tumor spheres. Treatment with Interferon-Beta (IFNb) led to a less aggressive epithelial/non-CSC-like state, with repressed expression of mesenchymal proteins (VIMENTIN, SLUG), reduced migration and tumor sphere formation, and re-expression of CD24 (a surface marker for non-CSCs), concomitant with an epithelial-like morphology. The CSC-like properties were correlated with high levels of unphosphorylated Interferon Stimulated Gene Factor 3 (U-ISGF3), which was previously linked to resistance to DNA damage. Inhibiting the expression of IRF9 (the DNA-binding component of U-ISGF3) reduced the migration of mesenchymal/CSCs. Here we report a positive translational role for IFNb as gene expression profiling of patient derived TNBC tumors demonstrates that an IFNb Metagene signature correlates with improved patient survival, an immune response linked with Tumor Infiltrating Lymphocytes (TILs) and a repressed CSC Metagene signature. Taken together, our findings indicate that repressed IFN signaling in TNBCs with CSC-like properties is due to high levels of U-ISGF3, and that treatment with IFNb reduces CSC properties, suggesting a novel therapeutic strategy to treat drug-resistant, highly aggressive TNBC tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106782 | GEO | 2017/11/12

SECONDARY ACCESSION(S): PRJNA418007

REPOSITORIES: GEO

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Project description:Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that promotes higher risk of metastasis and cancer reoccurrence, subsequently reduces survival rate of cancer patients. Cisplatin is one of the potential anticancer drugs for treating TNBC. However, occurrence of cisplatin resistance still remains as one of the challenges to fully eradicate TNBC. Since presence of cancer stem cells (CSCs) often known as one of the contributors of drug resistance, investigation has been conducted, suggesting sorted CSC-like subpopulation to be more resistant to cisplatin as compared to parental cells, alongside with higher self-renewability. On the other hand, plethora evidences showed the transmission of exosomal-miRNAs are capable of promoting drug resistance in breast cancers. In this study, we aim to elucidate the differential expression of exosomal-microRNAs profile and reveal the potential target genes in correlation to cisplatin resistance associated with CSC-like subpopulation by using TNBC cell line (MDA-MB-231). Utilizing next generation sequencing and Nanostring techniques, cisplatin-induced dysregulation of exosomal-miRNAs were evaluated in maximal for CSC-like subpopulation as compared to parental cells. Intriguingly, cisplatin induced a relatively oncogenic exosomal-miRNAs profile derived from treated CSC-like subpopulation as compared to treated parental cells, which may correlate to enhancement of drug resistance and maintenance of CSCs. Among the detected exosomal-miRNA profile in treated CSC-like subpopulation, unique clusters of miRNAs namely miR-221-3p, miR-196a-5p, miR-17-5p and miR-126-3p were predicted to target on six genes (ATXN1, LATS1, GSK3β, ITGA6, JAG1 and MYC), aligned with previous finding which demonstrated dysregulation of these genes in treated CSC-like subpopulation. Our results highlight the potential correlation of exosomal-miRNAs and their target genes as well as novel perspectives of the corresponding pathways that may be essential to contribute to the attenuated cytotoxicity of cisplatin in CSC-like subpopulation.

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Genome-wide analysis of gene expression by IFNβ in Transformed HMEC (Epithelial/non-CSC, Mesenchymal/CSC)

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