研究通过实验定量分析了乳腺癌模型中血液和肿瘤组织中miRNA的表达变化，发现miR-10b在脂肪垫肿瘤中显著高于皮下，且在淋巴结疾病中水平最高。未检测到miR-10b在血液中，而miR-221在肿瘤组织中显著增加。miR-195和miR-497在肿瘤组织及3周后的血液中下降，并存在显著相关性。此外，47种miRNA在疾病进程中有显著变化，其中10种作为潜在的新型标志物被验证。这项工作揭示了miRNA在乳腺癌中的作用，并强调了寻找血液循环中新的癌症标志物的重要性。
摘要：
Introduction: MiRNAs are aberrantly expressed in both the circulation and tissue of patients with breast tumours, however little is currently known about the relationship between circulating and tissue miRNAs. The aim of this study was to quantify circulating and tumour tissue miRNA expression in a murine model of breast cancer and identify novel circulating markers of disease progression.Materials and Methods: Athymic nude mice (n = 20) received either a mammary fat pad (n = 8, MFP), or subcutaneous (n = 7, SC) injection of MDA-MB-231 cells. Controls received no tumour cells (n = 5). Tumour volume was monitored weekly and blood sampling performed at weeks 1, 3 and 6 following tumour induction (total n=60). Animals were sacrificed at week 6 and tumour tissue (n = 15), lungs (n = 20) and enlarged lymph nodes (n = 3) harvested. RNA were extracted from all samples (n = 98) and relative expression of miRNAs previously associated with tumour progression were quantified using RQ-RCR. A microRNA array was also preformed comparing animals with early (weeks 1, n=5) versus late (week 6, n=5) disease and results were analysed using RQ-PCR in all blood samples (n = 60). Reverse transcription for the relevant targets and endogenous controls was carried out and expression was quantified using RQ-PCR.Results: MiR-10b expression was significantly higher in MFP compared to SC tumours (p < 0.05), with the highest levels in diseased lymph nodes (p < 0.05). MiR-10b was undetectable in the circulation. MiR-221 expression was significantly increased in tumour tissue (p < 0.001). MiR-195 and miR-497 were significantly decreased in tumour tissue (p < 0.05), and also in the circulation of animals 3 weeks following tumour induction (p < 0.05). At both tissue and circulating level, a significant correlation was observed between miR-497 and miR-195 (r = 0.61, p < 0.001; r = 0.41, p < 0.01 respectively). Microarray analysis revealed the level of 47 miRs to be significantly changed between week 1 and week 6 as disease progressed in a murine model, 10 of which (miR A-J) were significantly altered and internally validated within the murine model.Conclusions: This study highlights the importance of miRNAs in breast cancer, with each displaying distinct roles in circulation and tissue. Novel circulating miRNAs which have never previously been associated with breast cancer have been identified, with quantification of circulating levels in breast cancer patients currently ongoing.Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-09.
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