Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers

Abstract

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

“…4 Using 3C, we (B) Intron-exon structures of CUPID1 and CUPID2 transcripts identified by RNA CaptureSeq in MCF7 cells with or without estrogen stimulation. RefSeq lncRNA gene LINC01488 (CUPID1) and predicted lncRNA AP000439.3 (CUPID2) are shown in green, and CUPID1 and CUPID2 transcripts verified by PCR in MCF7 cells are indicated by red arrows ( Figure S2).…”

“…4 However, cyclin D1 also plays a role in HR-mediated DNA repair (HRR), a function independent of its role in cell-cycle control. 28 Given this and the fact that pathway analyses indicated that CUPID1-and CUPID2-regulated genes affect DNA repair and recombination, we hypothesized that PRE1 might act as an enhancer of other genes in the HRR pathway, including CUPID1 and CUPID2.…”

“…Several studies have shown that GWAS SNPs are enriched in regulatory regions and can influence the expression of nearby protein-coding genes. [3][4][5][6] However, the contribution of noncoding RNAs to disease risk is still relatively unexplored, partly because noncoding RNAs are poorly annotated.…”

“…We previously fine-mapped this locus and found that the strongest genetic signal contained four SNPs located within a distal transcriptional enhancer (called PRE1) of CCND1 (MIM: 168461). 4 Here, we have identified two long noncoding RNAs (lncRNAs) transcribed from this region and name them CUPID1 and CUPID2 (CCND1-upstream intergenic DNA repair 1 and 2). We have found that PRE1 acts as a strong enhancer on the bidirectional promoter of CUPID1 and CUPID2.…”

Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects onDIS3expression

“…Independent loci for breast and renal cancer have been shown to interact with the promoter of the cyclin D (CCND1) gene located $130 and $216 kb downstream, and possibly regulate its expression in an allele-specific manner (43,44).…”