Germline Genetic Variants Disturbing the Let-7/LIN28 Double-Negative Feedback Loop Alter Breast Cancer Susceptibility

Abstract

Previous studies have shown that let-7 can repress the post-transcriptional translation of LIN28, and LIN28 in turn could block the maturation of let-7, forming a double-negative feedback loop. In this study, we investigated the effect of germline genetic variants on regulation of the homeostasis of the let-7/LIN28 loop and breast cancer risk. We initially demonstrated that the T/C variants of rs3811463, a single nucleotide polymorphism (SNP) located near the let-7 binding site in LIN28, could lead to differential regulation of LIN28 by let-7. Specifically, the C allele of rs3811463 weakened let-7–induced repression of LIN28 mRNA, resulting in increased production of LIN28 protein, which could in turn down-regulate the level of mature let-7. This effect was then validated at the tissue level in that the normal breast tissue of individuals with the rs3811463-TC genotype expressed significantly lower levels of let-7 and higher levels of LIN28 protein than those individuals with the rs3811463-TT genotype. Because previous in vitro and ex vivo experiments have consistently suggested that LIN28 could promote cellular transformation, we then systematically evaluated the relationship between rs3811463 as well as other common LIN28 SNPs and the risk of breast cancer in a stepwise manner. The first hospital-based association study (n = 2,300) demonstrated that two SNPs were significantly associated with breast cancer risk, one of which was rs3811463, while the other was rs6697410. The C allele of the rs3811463 SNP corresponded to an increased risk of breast cancer with an odds ratio (OR) of 1.25 (P = 0.0091), which was successfully replicated in a second independent study (n = 1,156) with community-based controls. The combined P-value of the two studies was 8.0×10−5. Taken together, our study demonstrates that host genetic variants could disturb the regulation of the let-7/LIN28 double-negative feedback loop and alter breast cancer risk.

Association Between the Pre-mir-218 Polymorphism and Cancer Risk in the Chinese Population: a Meta-Analysis

“…MiRNAs include primary, precursor and mature miRNA, in which single nucleotide polymorphisms (SNPs) of these miRNAs may improve miRNA binding affinity and change mRNA expression levels of the target genes, thus leading to cancer susceptibility (Liu et al, 2011;Chen et al, 2011). Zhou (2010) and Shi found that the pri-miR-218 rs11134527 SNP was significantly associated with the risk of cervical carcinoma in Chinese women.…”

Enriched variations in TEKT4 and breast cancer resistance to paclitaxel

“…Breast cancer cell lines (MDA-MB-468, MDA-MB-231, MCF7, ZR-75-1, BT-474, MDA-MB-435, SK-BR-3 and Hs578T), normal breast MCF-10A cells and 293T cells were obtained from the American Type Culture Collection (Manassas, VA, USA) and maintained in complete growth medium as described previously 39,47 . Liquid nitrogen stocks were created upon receipt, and cells were maintained until the start of each study.…”

Genetic variation of rs3811463 is associated with gestational diabetes mellitus susceptibility

“…SNPs are the major type of human genomic variation. Among Han Chinese woman, three SNPs (rs4659441, rs3811463 and rs6697410) were detected in the 3'UTR of Lin28, and allelic variation of rs3811463 influenced let-7-related regulation of Lin28 expression (12). Previous studies showed that insulin resistance and defects in insulin secretion play key roles in the etiology of both GDM and T2DM.…”

“…A SNP located near the let-7 binding site in Lin28, the T/C variants of rs3811463 could lead to differential regulation of Lin28 by let-7 (12). The rs3811463 polymorphism in the let-7/Lin28 pathway significantly increased the risk of T2DM (13).…”