復旦大學附屬腫瘤醫(yī)院、復旦大學乳腺癌研究所的最新研究深入探討了乳腺癌干細胞相關微小RNA（microRNA）let-7,，與腫瘤惡性轉化相關基因LIN28形成的LIN28/let-7雙向負反饋調控環(huán)的基因變異在乳腺癌發(fā)生中的作用,。研究首次揭示了LIN28的3’非翻譯區(qū)多態(tài)位點參與LIN28/let-7反饋環(huán)的生物學調控，調節(jié)LIN28和let-7的基因表達,；尤為重要的是，多態(tài)效應通過雙向負反饋環(huán)得到級聯(lián)擴增,。該項成果為臨床尋找乳腺癌高危女性提供了參考,，也為let-7這一乳腺癌“干性”調控microRNA在生理條件下如何影響LIN28/let-7環(huán)的基因差異表達提供了遺傳學基礎,。
該研究由邵志敏教授領銜的乳腺癌易感性研究課題組完成。課題組立足于中國人群乳腺癌和正常對照的DNA及組織樣本,，系統(tǒng)分析了中國人群的基因突變和基因變異,，取得了如BRCA1/2突變在中國家族性、早發(fā)性乳腺癌中的流行病情況,，p53基因的變異熱點和功能學改變,，以及散發(fā)性乳腺癌中雌醌代謝酶基因多態(tài)性對乳腺癌發(fā)生的作用等一系列研究成果。本次針對LIN28/let-7環(huán)遺傳變異的研究,，是對散發(fā)性乳腺癌遺傳易感性研究的有力補充,，提示microRNA相關多態(tài)在乳腺癌發(fā)生發(fā)展中的地位。當前,，乳腺癌高危人群篩查,、腫瘤風險預測成為乳腺癌預防中的重要任務，本成果為尋找乳腺癌特異性預測位點提供了臨床前基礎,。項目獲得國家自然科學基金面上項目的資助,。(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.
