A variant affecting a putative miRNA target site in estrogen receptor (ESR) 1 is associated with breast cancer risk in premenopausal women.
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.
Tchatchou
Sandrine
S
Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. s.tchatchou@dkfz.de
Jung
Anke
A
Hemminki
Kari
K
Sutter
Christian
C
Wappenschmidt
Barbara
B
Bugert
Peter
P
Weber
Bernhard H F
BH
Niederacher
Dieter
D
Arnold
Norbert
N
Varon-Mateeva
Raymonda
R
Ditsch
Nina
N
Meindl
Alfons
A
Schmutzler
Rita K
RK
Bartram
Claus R
CR
Burwinkel
Barbara
B
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
D047628:Estrogen Receptor alpha; D035683:MicroRNAs