Volinia Stefano, Bertagnolo Valeria, Grassilli Silvia, Brugnoli Federica, Manfrini Marco, Galasso Marco, Scatena Cristian, Mazzanti Chiara Maria, Lessi Francesca, Naccarato Giuseppe, Caligo Adelaide, Bianchini Enzo, Piubello Quirino, Orvieto Enrico, Rugge Massimo, Natali Cristina, Reale Domenico, Vecchione Andrea, Warner Sarah, Croce Carlo Maria, Capitani Silvano
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy.
LTTA Centre, University of Ferrara, Ferrara 44121, Italy.
Oncotarget. 2018 May 4;9(34):23543-23553. doi: 10.18632/oncotarget.25261.
A substantial number of ductal carcinoma (DCIS) detected by mammography never progress to invasive ductal carcinoma (IDC) and current approaches fail to identify low-risk patients not at need of adjuvant therapies. We aimed to identify the key miRNAs protecting DCIS from malignant evolution, that may constitute markers for non-invasive lesions. We studied 100 archived DCIS samples, including pure DCIS, DCIS with adjacent IDC and pure DCIS from patients with subsequent IDC in contralateral breast or no recurrence. A DCIS derived cell line was used for molecular and cellular studies. A genome wide study revealed that pure DCIS has higher miR-126 and miR-218 expression than DCIS with adjacent IDC lesions or than IDC. The down-regulation of miR-126 and miR-218 promoted invasiveness and, in patients with pure DCIS, was associated with later onset of IDC. Survival studies of independent cohorts indicated that both miRNAs play a protective role in IDC. The clinical findings are in agreement with the miRNAs' roles in cell adhesion, differentiation and proliferation. We propose that miR-126 and miR-218 have a protective role in DCIS and represent novel biomarkers for the risk assessment in women with early detection of breast cancer.
通过乳房X线摄影检测出的大量导管原位癌（DCIS）从未进展为浸润性导管癌（IDC），而目前的方法无法识别出不需要辅助治疗的低风险患者。我们旨在确定保护DCIS免于恶性进展的关键微小RNA（miRNA），这些miRNA可能构成非侵袭性病变的标志物。我们研究了100份存档的DCIS样本，包括单纯DCIS、伴有相邻IDC的DCIS以及来自对侧乳房发生后续IDC或无复发患者的单纯DCIS。使用一种源自DCIS的细胞系进行分子和细胞研究。一项全基因组研究显示，单纯DCIS的miR-126和miR-218表达高于伴有相邻IDC病变的DCIS或IDC。miR-126和miR-218的下调促进了侵袭性，在单纯DCIS患者中，与IDC的较晚发病相关。对独立队列的生存研究表明，这两种miRNA在IDC中均发挥保护作用。临床研究结果与miRNA在细胞黏附、分化和增殖中的作用一致。我们提出，miR-126和miR-218在DCIS中具有保护作用，并代表了早期乳腺癌检测女性风险评估的新型生物标志物。
