复旦大学附属肿瘤医院、复旦大学乳腺癌研究所的最新研究深入探讨了乳腺癌干细胞相关微小RNA（microRNA）let-7，与肿瘤恶性转化相关基因LIN28形成的LIN28/let-7双向负反馈调控环的基因变异在乳腺癌发生中的作用。研究首次揭示了LIN28的3’非翻译区多态位点参与LIN28/let-7反馈环的生物学调控，调节LIN28和let-7的基因表达；尤为重要的是，多态效应通过双向负反馈环得到级联扩增。该项成果为临床寻找乳腺癌高危女性提供了参考，也为let-7这一乳腺癌“干性”调控microRNA在生理条件下如何影响LIN28/let-7环的基因差异表达提供了遗传学基础。
该研究由邵志敏教授领衔的乳腺癌易感性研究课题组完成。课题组立足于中国人群乳腺癌和正常对照的DNA及组织样本，系统分析了中国人群的基因突变和基因变异，取得了如BRCA1/2突变在中国家族性、早发性乳腺癌中的流行病情况，p53基因的变异热点和功能学改变，以及散发性乳腺癌中雌醌代谢酶基因多态性对乳腺癌发生的作用等一系列研究成果。本次针对LIN28/let-7环遗传变异的研究，是对散发性乳腺癌遗传易感性研究的有力补充，提示microRNA相关多态在乳腺癌发生发展中的地位。当前，乳腺癌高危人群筛查、肿瘤风险预测成为乳腺癌预防中的重要任务，本成果为寻找乳腺癌特异性预测位点提供了临床前基础。项目获得国家自然科学基金面上项目的资助。(生物谷Bioon.com)
doi:10.1001/archinternmed.2011.356
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Germline Genetic Variants Disturbing the Let-7/LIN28 Double-Negative Feedback Loop Alter Breast Cancer Susceptibility
Ao-Xiang Chen#, Ke-Da Yu#, Lei Fan, Ji-Yu Li, Chen Yang, A-Ji Huang, Zhi-Ming Shao*
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.
