microRNAs (miRNAs) are 17-nt to 24-nt short non-coding RNAs that have emerged as criti- cal regulators of gene expression in almost all forms of life. miRNAs act by partial comple- mentary binding usually within the 3'-untranslated region (3'UTR) of the mRNA target result- ing in translational repression and/or mRNA degradation. Microarray and proteomic experi- ments have demonstrated the impact of a single miRNA on fine-tuning expression of a hun- dred of targets affecting a multitude of biological processes such as development, prolifera- tion and apoptosis. Deregulation of miRNA function is also implicated in various diseases including the development of cancer. Furthermore, recent miRNA profiling studies conducted on different tumor types have identified sets of miRNAs that have altered expression in tumor and normal tissue, making them attractive targets for therapeutic intervention or as diagnos- tic markers. Nevertheless, target identification and detailed knowledge of miRNA functions is the key for the correct selection of miRNAs causally involved in the specific disease process. This SEARCH focuses especially on the role of miRNAs in two processes that are of major in- terest to breast cancer research; the ErbB2/ErbB3/Akt signaling pathway and cancer cell motility. Prolonged ErbB2/ErbB3/Akt signaling is frequently reported in various cancers and enables the cell to bypass targeting therapies as it favors cell survival. In the case of breast cancer, this is particularly achieved by increased ErbB2/ErbB3 receptor activation. In order to investigate the extent by which miRNAs modulate the ErbB receptor signaling pathway, we performed a genome-wide screen in the breast cancer cell line MCF7 based on Akt phos- phorylation as a read-out. We identified 43 miRNAs that specifically regulate heregulin (HRG)-induced Akt activation, either positively or negatively, and revealed the complexity of coordinated miRNA-target interactions within the ErbB signaling pathway. We further validat- ed four miRNAs, miR-149, miR-148b, miR-326, and miR-520a-3p, with potential tumor sup- pressive function as novel regulators of ErbB3 transcript and protein levels. But also the ex- pression levels of other key components within the ErbB/Akt pathway were affected either on the protein or mRNA level, like Erk1/2 and PIK3CA. The selected miRNAs further efficiently
د محمد محمود محمد عبد الفتاح | DR MOHAMMAD MAHMOUD MOHAMMAD ADEL FATAH | 9780