Abstract
A substantial number of ductal carcinoma in situ (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 in vitro 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.
Highlights
Breast cancer (BC) is characterized by several histological and genetic distinctive features, which lead to substantial differences in treatment and clinical outcomes [1, 2]
The miRNA-Seq profiles were compared to those of other Ductal carcinoma in situ (DCIS) from the Farazi’s cohort [17] and of invasive ductal carcinoma (IDC) from the TCGA cohort. miR-125b, miR-126, miR218 and miR-195 were over-expressed in DCIS vs. IDC (P < 0.001) and their over-expression was confirmed in the small Farazi DCIS cohort (P < 0.001) (Figure 1A)
Among these miRNAs we successfully cross-validated miR-126 and miR-218 when using the samples from the Norway study by Sorlie and coworkers [12] (Supplementary Figure 1). miR-210 was previously reported to be associated with DCIS malignant transition [18] and this study confirmed its over-expression in DCIS with respect to normal tissues (P < 0.001), but not to IDC (Figure 1A)
Summary
Breast cancer (BC) is characterized by several histological and genetic distinctive features, which lead to substantial differences in treatment and clinical outcomes [1, 2]. After the advent of screening mammography, the proportion of detected early carcinomas increased substantially and only 20% of them were expected to progress, which implied a high number of over-diagnosed lesions [3]. Ductal carcinoma in situ (DCIS) represents 20–25% of newly diagnosed BC in industrialized countries and up to 40% of DCIS lesions progress to invasive carcinoma (IDC) if untreated [4]. To IDC, DCIS is a heterogeneous group of breast lesions and the potential for progression to invasive carcinoma varies among the molecular subtypes [5,6,7,8,9]. The evaluation of clinical biomarkers in adjacent DCIS and IDC allowed determining that different degrees of aggressiveness characterize DCIS lesions with high heterogeneity in the same patient. The intracellular pathways that control progression to IDC are still largely unknown, making it difficult to identify either robust biomarkers or therapeutic targets for DCIS
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