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Germline genetic variants disturbing the Let-7/LIN28 double-negative feedback loop alter breast cancer susceptibility
Ao-Xiang Chen1, Ke-Da Yu, Lei Fan
1Department of Breast Surgery, Cancer Center, and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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.
Insights
Genetic variants in the let-7/LIN28 feedback loop influence breast cancer risk. A specific SNP, rs3811463, disrupts this loop, increasing LIN28 protein and lowering let-7 levels, thereby elevating breast cancer risk.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- The let-7/LIN28 pathway forms a double-negative feedback loop regulating gene expression.
- LIN28 is implicated in cellular transformation and cancer development.
- Germline genetic variants may influence the homeostasis of this critical regulatory loop.
Purpose of the Study:
- To investigate the impact of germline genetic variants on the let-7/LIN28 feedback loop.
- To determine the association between these variants and breast cancer risk.
Main Methods:
- Analysis of single nucleotide polymorphisms (SNPs) near the let-7 binding site in LIN28, specifically rs3811463.
- Validation of SNP effects on let-7 and LIN28 levels in normal breast tissue.
- Case-control association studies to evaluate the relationship between LIN28 SNPs and breast cancer risk.
Main Results:
- The rs3811463 T/C variant weakens let-7 repression of LIN28 mRNA, increasing LIN28 protein and decreasing mature let-7 levels.
- Individuals with the TC genotype showed lower let-7 and higher LIN28 in breast tissue.
- The C allele of rs3811463 was significantly associated with increased breast cancer risk (OR=1.25, P=0.0091), replicated in an independent study.
Conclusions:
- Germline genetic variants can disrupt the let-7/LIN28 double-negative feedback loop.
- Specific variants, like rs3811463, are linked to altered breast cancer risk.
- This highlights the role of genetic predisposition in cancer development through regulatory pathway disruption.
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