title: A variant affecting a putative miRNA target site in estrogen receptor (ESR) 1 is associated with breast cancer risk in premenopausal women.
abstract: MicroRNAs (miRNAs) negatively regulate expression of target transcripts by hybridization to complementary sites of their messenger RNA targets. Chen et al. have described several putative functional single nucleotide polymorphisms (SNPs) in miRNA target sites. Here, we selected 11 miRNA target site SNPs located in 3' untranslated regions of genes involved in cancer and breast cancer to analyze their impact on breast cancer risk using a large familial study population. Whereas no association was observed for 10 SNPs, a significant association was revealed for the variant affecting a miRNA target site in the estrogen receptor (ESR) 1. Age stratification showed that the association was stronger in premenopausal women [C versus T: odds ratio (OR) = 0.60, confidence interval (CI) = 0.41-0.89, P = 0.010]. Furthermore, the effect was stronger in high-risk familial cases (C versus T: OR = 0.42, CI = 0.25-0.71, P = 0.0009). Clinical studies have shown that elimination of ESR1 significantly reduces breast cancer risk. Thus, therapies that inhibit ESR1 are used for breast cancer treatment. According to in silico analysis, ESR1_rs2747648 affects the binding capacity of miR-453, which is stronger when the C allele is present. In contrast, the T allele attenuates the binding of miR-453, which might lead to a reduced miRNA-mediated ESR1 repression, in consequence higher ESR1 protein levels and an increased breast cancer risk. Thus, the breast cancer protective effect observed for the C allele in premenopausal women is biologically reasonable. The analysis of large study populations in multicentre collaboration will be needed to verify the association and answer questions regarding the possible impact of this variant on therapeutic and clinical outcome.
authors.affiliation: Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. s.tchatchou@dkfz.de
authors.forename: Sandrine
authors.initials: S
authors.lastname: Tchatchou
authors.forename: Anke
authors.initials: A
authors.lastname: Jung
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Christian
authors.initials: C
authors.lastname: Sutter
authors.forename: Barbara
authors.initials: B
authors.lastname: Wappenschmidt
authors.forename: Peter
authors.initials: P
authors.lastname: Bugert
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
authors.forename: Dieter
authors.initials: D
authors.lastname: Niederacher
authors.forename: Norbert
authors.initials: N
authors.lastname: Arnold
authors.forename: Raymonda
authors.initials: R
authors.lastname: Varon-Mateeva
authors.forename: Nina
authors.initials: N
authors.lastname: Ditsch
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Rita K
authors.initials: RK
authors.lastname: Schmutzler
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017697:Premenopause
chemical_list: D047628:Estrogen Receptor alpha; D035683:MicroRNAs