title: Tumor-promoting function of single nucleotide polymorphism rs1836724 (C3388T) alters multiple potential legitimate microRNA binding sites at the 3'-untranslated region of ErbB4 in breast cancer.
abstract: ErbB4 can act as either a tumor-suppressor gene or an oncogene in breast cancer. Multiple genetic factors including single nucleotide polymorphisms (SNPs) affect gene expression patterns. Multiple 3'-untranslated region (3'-UTR) SNPs reside within the target binding site of microRNAs, which can strengthen or weaken binding to target genes. The present study aimed to predict potential 3'‑UTR variants of ErbB4 that alter the target binding site of microRNAs (miRNAs) and to clarify the association of the potential variant with the risk of developing breast cancer. In silico prediction was performed to identify potential functional SNPs within miRNA target binding sites in the 3'‑UTR of ErbB4. Thus, 146 patients and controls were genotyped using restriction fragment length polymorphism-polymerase chain reaction. In addition to the Cochran-Armitage test for trend, allele and genotype frequency differences were determined to investigate the association between rs1836724 and the susceptibility to breast cancer. Bioinformatics analysis identified rs1836724 to be a polymorphism in the seed region of four miRNA binding sites (hsa-miR335-5p, hsa-miR-28-5p, has‑miR‑708‑5p and has‑miR‑665), which may participate in the development of breast cancer. Logistic regression data indicated that the T allele of the polymorphism [OR (95% CI)=1.72 (1.056‑2.808), P=0.029] is associated with the risk of breast cancer. Using bioinformatics tools, a correlation was indicated between the presence of the T allele and a reduction in ErbB4 RNA silencing based on miRNA interaction. Furthermore, case subgroup data analysis revealed an association between the C/T genotype and an ER positive phenotype [OR (95% CI)=6.00 (1.082‑33.274), P=0.028] compared with the T/T genotype. ErbB4 and estrogen receptor 1 (ESR1) are regulated by identical miRNAs thus there may be a competition for binding sites. Due to this pattern, if the interaction between miRNAs with one gene is reduced, it may be consistent with the increase in interaction with another one. Therefore, more interaction with rs1836724 C variant within ErbB4 may be associated with higher expression of ESR1 (ER‑positive phenotype). miRNAs interact with ErbB4 mRNA more frequently when it carries C allele at the rs1836724 position compared with the T carriers. Therefore, the identical miRNA interacts with ESR1 less frequently when ErbB4 mRNA has a C allele. Therefore, ESR1 expression may be higher when ErbB4 mRNA has a C allele.
authors.affiliation: Biochemistry Division, Department of Biology, Faculty of Science, Payame Noor University of Taft, Yazd 47416‑95447, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Bagheri
authors.affiliation: Cellular and Molecular Biology Division, Department of Biology, Faculty of Science, University of Isfahan, Isfahan 81746‑73441, Iran.
authors.forename: Hamzeh
authors.initials: H
authors.lastname: Mesrian Tanha
authors.affiliation: Genetics Division, Department of Biology, Faculty of Science, University of Isfahan, Isfahan 81746‑7344, Iran.
authors.forename: Marjan
authors.initials: M
authors.lastname: Mojtabavi Naeini
authors.affiliation: Cellular and Molecular Biology Division, Department of Biology, Faculty of Science, University of Isfahan, Isfahan 81746‑73441, Iran.
authors.forename: Kamran
authors.initials: K
authors.lastname: Ghaedi
authors.affiliation: Zist Fanavary Novin Institute, Isfahan 14115‑111, Iran.
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Azadeh
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D012334:RNA, Neoplasm; C587689:ERBB4 protein, human; D066247:Receptor, ErbB-4