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Simple Summary  Previous research has revealed a genetic predisposition to breast carcinogenesis. Thus, identifying causal genetic variants and their associated gene networks may improve breast cancer diagnostics and risk assessment. Our study investigated  YBEY , an uncharacterized gene in humans, and its functions in breast cancer risk and progression. We identified two genetic variants associated with  YBEY  expression that may have causal functions in breast cancer risk. We performed in vitro functional assays using MCF-7, T47D, and MDA-MB-231 breast cancer cell lines and showed that knockdown of  YBEY  expression significantly inhibited proliferation, colony formation, and invasion/migration. We utilized RNA sequencing to identify gene networks associated with  YBEY  knockdown including inflammation and metabolic pathways. Further, we used data available in The Cancer Genome Atlas to explore trends in  YBEY  expression patterns in normal and tumor tissues. Our study provides a role for  YBEY  in breast carcinogenesis, and further studies investigating its mechanistic functions are warranted.    Abstract  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, r 2  > 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 .

Functional Genomic Analyses of the 21q22.3 Locus Identifying Functional Variants and Candidate Gene YBEY for Breast Cancer Risk