Identification of stable markers of EGFR inhibitor resistance in breast cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE140978 | GEO | 2020/12/01
REPOSITORIES: GEO
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Project description:Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) facilitate breast cancer (BC) metastasis, however stable molecular changes that result as a consequence of these processes remain poorly defined. Therefore, we sought to identify molecular markers that could distinguish tumor cells that had completed the EMT:MET cycle in the hopes of identifying and targeting unique aspects of metastatic tumor outgrowth.Therefore, normal murine mammary gland (NMumG) cells transformed by overexpression of EGFR (NME) cells were cultured in the presence of TGF-beta1 (5 ng/ml) for 4 weeks, at which point TGF-beta1 supplementation was discontinued and the cells were allowed to recover for an additional 4 weeks (Post-TGF-Rec). Total RNA was prepared from unstimulated cells (Pre-TGF) of similar passage and compared by microarray analysis. The two groups were analyzed in triplicate, three Pre-TGF samples and three Post-TGF-Rec samples.
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Project description:Approximately 15% of lung cancer cases are not associated with smoking and show molecular and clinical characteristics distinct from those in smokers. Epidermal growth factor receptor (EGFR) gene mutations, which are correlated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), are more frequent in never-smoker lung cancers. In this study, microRNA (miRNA) expression profiling of 28 never-smoker lung cancer cases identified aberrantly expressed miRNAs, which were much fewer than in lung cancers of smokers and included miRNAs previously identified (e.g., upregulated miR-21) and unidentified (e.g., downregulated miR-138) in those smoker cases. The changes in expression of some of these miRNAs were more remarkable in cases with EGFR mutations than in those without: the most upregulated miRNA, miR-21, was more abundant in cancers with EGFR mutation. A significant correlation between phosphorylated-EGFR (p-EGFR) and miR-21 levels in lung carcinoma cell lines and the suppression of miR-21 by an EGFR-TKI, AG1478, suggested that the EGFR signaling pathway positively regulated miR-21 expression. In a never-smoker-derived lung adenocarcinoma cell line H3255 with mutant EGFR and high levels of p-EGFR and miR-21, antisense inhibition of miR-21 enhanced AG1478-induced apoptosis. In a never-smoker-derived adenocarcinoma cell line H441 with wild-type EGFR, the antisense miR-21 not only showed the additive effect with AG1478 but also induced apoptosis by itself. These results suggest that aberrantly increased expression of miR-21, which is further enhanced by the activated EGFR signaling pathway, plays a critical role in lung carcinogenesis in never-smokers and is a potential therapeutic target in both EGFR mutant and wild-type cases.
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