We previously identified a locus at 21q22.3, tagged by the single nucleotide polymorphism (SNP) rs35418111, being associated with
breast cancer risk at a genome-wide significance level; however, the underlying causal functional variants and gene(s) responsible for this association are unknown. We performed functional genomic analyses to identify potential functional variants and target genes that may mediate this association. Functional annotation for SNPs in high linkage disequilibrium (LD, r2 > 0.8) with rs35418111 in Asians showed evidence of promoter and/or enhancer activities, including rs35418111, rs2078203, rs8134832, rs57385578, and rs8126917. These five variants were assessed for interactions with
nuclear proteins by electrophoretic mobility shift assays. Our results showed that the risk alleles for rs2078203 and rs35418111 altered
DNA-
protein interaction patterns. Cis-expression quantitative loci (cis-eQTL) analysis, using data from the Genotype-Tissue Expression database (GTEx) European-ancestry female normal breast tissue, indicated that the risk allele of rs35418111 was associated with a decreased expression of the YBEY gene, a relatively uncharacterized
endoribonuclease in humans. We investigated the
biological effects of YBEY on
breast cancer cell lines by transient knock-down of YBEY expression in MCF-7, T47D, and MDA-MB-231 cell lines. Knockdown of YBEY
mRNA in
breast cancer cell lines consistently decreased cell proliferation, colony formation, and migration/invasion, regardless of
estrogen receptor status. We performed
RNA sequencing in MDA-MB-231 cells transfected with
siRNA targeting YBEY and subsequent gene set enrichment analysis to identify gene networks associated with YBEY knockdown. These data indicated YBEY was involved in networks associated with
inflammation and metabolism. Finally, we showed trends in YBEY expression patterns in breast tissues from The
Cancer Genome Atlas (TCGA); early-stage breast
cancers had elevated YBEY expression compared with normal tissue, but significantly decreased expression in late-stage disease. Our study provides evidence of a significant role for the human YBEY gene in
breast cancer pathogenesis and the association between the rs35418111/21q22.3 locus and
breast cancer risk, which may be mediated through functional SNPs, rs35418111 and rs2078203, that regulate expression of YBEY.