title: Involvement of IGF-1R regulation by miR-515-5p modifies breast cancer risk among BRCA1 carriers.
abstract: Several lines of evidence indicate that sequence alterations within microRNA (miRNA)-binding sites can modify the binding to its target gene resulting in altered expression patterns. We hypothesized that a single nucleotide polymorphism (SNP) located in the miR-515-5p binding site of igf-1r gene may alter IGF-1R regulation, with consequent effects on breast cancer risk in BRCA1 mutation carriers. Computational prediction revealed that the rs28674628 SNP in the igf-1r 3' UTR is located within a predicted binding site for miR-515-5p. The effect of this SNP on breast cancer risk was evaluated by genotyping 115 Jewish Ashkenazi carriers of the 185delAG mutation in the BRCA1 gene using the Sequenom platform followed by Kaplan-Meier analysis. Additional data set of 378 Jewish BRCA1 carriers was analyzed to validate our results. MiRNA transfection, Western blot analysis, luciferase reporter assay, real time PCR, and immunohistochemistry were performed to assess direct regulation of igf-1r by miR-515-5p. We show direct regulation of IGF-1R by miR-515-5p. We identified that disrupting miR-515-5p and igf-1r 3' UTR binding by SNP may cause elevated IGF-1R protein levels. Interestingly, miR-515-5p is downregulated in tumor tissue compared to its non-neoplastic surrounding tissue while IGF-1R levels are elevated. This igf-1r SNP was found to be significantly associated with age at diagnosis of breast cancer in Jewish Ashkenazi BRCA1 mutation carriers. These findings support the hypothesis that a SNP located in igf-1r gene may alter miRNA regulation of IGF-1R, with a putative effect on BRCA1 penetrance and breast cancer risk.
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Gilam
authors.forename: Liat
authors.initials: L
authors.lastname: Edry
authors.forename: Efrat
authors.initials: E
authors.lastname: Mamluk-Morag
authors.forename: Dalia
authors.initials: D
authors.lastname: Bar-Ilan
authors.forename: Camila
authors.initials: C
authors.lastname: Avivi
authors.forename: David
authors.initials: D
authors.lastname: Golan
authors.forename: Yael
authors.initials: Y
authors.lastname: Laitman
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.forename: Noam
authors.initials: N
authors.lastname: Shomron
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007585:Jews / Q000235:genetics; D053208:Kaplan-Meier Estimate; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D020413:3' Untranslated Regions; C585821:MIRN515 microRNA, human; D035683:MicroRNAs; D017526:Receptor, IGF Type 1