Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
J Pathol. 2012 Jan;226(1):108-19. doi: 10.1002/path.2978. Epub 2011 Sep 26.
Invasive lobular carcinoma (ILC) of the breast, characterized by loss of E-cadherin expression, accounts for 5-15% of invasive breast cancers and it is believed to arise via a linear histological progression. Genomic studies have identified a clonal relationship between ILC and concurrent lobular carcinoma in situ (LCIS) lesions, suggesting that LCIS may be a precursor lesion. It has been shown that an LCIS diagnosis confers a 15-20% risk of progression to ILC over a lifetime. Currently no molecular test or markers can identify LCIS lesions likely to progress to ILC. Since microRNA (miRNA) expression changes have been detected in a number of other cancer types, we explored whether their dysregulation might be detected during progression from LCIS to ILC. Using the Illumina miRNA profiling platform, designed for simultaneous analysis of 470 mature miRNAs, we analysed the profiles of archived normal breast epithelium, LCIS lesions found alone, LCIS lesions concurrent with ILC, and the concurrent ILCs as a model of linear histological progression towards ILC. We identified two sets of differentially expressed miRNAs, the first set highly expressed in normal epithelium, including hsa-miR-224, -139, -10b, -450, 140, and -365, and the second set up-regulated during lobular neoplasia progression, including hsa-miR-375, -203, -425-5p, -183, -565, and -182. Using quantitative RT-PCR, we validated a trend of increasing expression for hsa-miR-375, hsa-miR-182, and hsa-miR-183 correlating with ILC progression. As we detected increased expression of hsa-miR-375 in LCIS lesions synchronous with ILC, we sought to determine whether hsa-miR-375 might induce phenotypes reminiscent of lobular neoplasia by expressing it in the MCF-10A 3D culture model of mammary acinar morphogenesis. Increased expression of hsa-miR-375 resulted in loss of cellular organization and acquisition of a hyperplastic phenotype. These data suggest that dysregulated miRNA expression contributes to lobular neoplastic progression.
乳腺浸润性小叶癌（ILC）的特征是 E-钙黏蛋白表达缺失，约占浸润性乳腺癌的 5-15%，据信它是通过线性组织学进展而发生的。基因组研究已经确定了 ILC 与同时存在的小叶原位癌（LCIS）病变之间的克隆关系，这表明 LCIS 可能是一种前体病变。已经表明，LCIS 的诊断会导致一生中发生 ILC 的风险增加 15-20%。目前，没有分子测试或标记物可以识别可能进展为 ILC 的 LCIS 病变。由于在许多其他癌症类型中已经检测到 microRNA（miRNA）表达的改变，我们探讨了它们的失调是否可能在 LCIS 进展为 ILC 期间被检测到。我们使用 Illumina miRNA 分析平台，该平台专为同时分析 470 个成熟 miRNA 而设计，分析了存档的正常乳腺上皮、单独存在的 LCIS 病变、LCIS 病变与 ILC 并存的组织以及作为向 ILC 线性组织学进展的模型的 ILC 样本的 miRNA 图谱。我们确定了两组差异表达的 miRNA，第一组在正常上皮中高表达，包括 hsa-miR-224、-139、-10b、-450、140 和 -365，第二组在小叶肿瘤进展过程中上调，包括 hsa-miR-375、-203、-425-5p、-183、-565 和 -182。通过定量 RT-PCR，我们验证了 hsa-miR-375、hsa-miR-182 和 hsa-miR-183 的表达呈上升趋势，与 ILC 进展相关。由于我们在与 ILC 同时存在的 LCIS 病变中检测到 hsa-miR-375 的表达增加，我们试图确定 hsa-miR-375 是否通过在 MCF-10A 3D 乳腺腺泡形态发生培养模型中表达而诱导出类似于小叶肿瘤的表型。hsa-miR-375 的表达增加导致细胞组织丧失并获得增生表型。这些数据表明，miRNA 表达失调有助于小叶肿瘤的进展。
