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ShRNA screening analysis of breast cancer

ABSTRACT: Background: We searched triple negative breast cancer (TNBC) specifically expressing candidates for target therapy. Methods: High expressing genes in three TNBC cell lines compared to three non-TNBC cell lines were evaluated by using RNA sequencing (log2 ratio>5, q<0.05). By integrating the shRNA library screening and public gene expression databases, we identifyied candidates for therapeutic targets. The expression significance of the candidates was examined by using immunohistochemistry of 248 clinical breast cancer patients. Results: One hundred seventy one genes were detected as highly expressed genes in TNBC cell lines than non-TNBC cell lines, and 13 genes were picked up as candidates not expressing in non-cancerous tissues. Integrated analysis with shRNA screening identified three candidates as TBNC specific molecular targets. Protein staining were stronger in breast cancer tissues, especially TNBC, than in the normal tissues.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113651 | GEO | 2019/02/27

REPOSITORIES: GEO

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Project description:Triple negative breast cancer (TNBC) is a highly heterogeneous disease representing the most aggressive breast cancer (BC) subtype. Lack of Estrogen Receptor alpha (ERα), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu) expression makes TNBC immune to common therapies, significantly limiting the treatment options and suggesting the need to identify novel therapeutic targets. It was previously reported that Estrogen Receptor beta (ERβ) is expressed in a fraction of TNBC patients, where its presence correlates with improved patient outcome. Recently, we demonstrated an oncosuppressive ERβ effect in TNBC cell models expressing exogenous ERβ. On the other hand, it was shown that ERβ is involved in miRNA-mediated gene regulation in hormone-responsive BC cells, suggesting similar effect also in TNBC. To verify this hypothesis, we performed small non-coding RNA (sncRNA) sequencing on three engineered cell lines belonging to different TNBC molecular subtypes. ERβ-specific changes of sncRNA profile revealed that the major part of deregulated molecules are subtype specific, with only few commonly regulated ones. In order to validate the obtained results, we performed sncRNA profiling of 12 ERβ positive and 32 ERβ negative TNBC tissues, whose receptor status was assessed by immunohistochemistry in our previous research. Also here, ERβ-specific group of deregulated sncRNAs was identified. Interestingly, comparison of obtained in vitro and in vivo results revealed 2 differentially expressed miRNAs, displaying the same behavior in all three analyzed cell lines and tissues. In concordance with our previous results, IPA signaling pathway analysis performed on genes targeted by deregulated miRNAs highlighted downregulation of cholesterol biosynthesis pathway and upregulation of several signaling processes. Taken together, these findings suggest that ERβ is able to exert its oncosuppressive role in TNBC through miRNA-mediated regulation of gene expression.

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ShRNA screening analysis of breast cancer

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