A microRNA Signature Associated with Early Recurrence in Breast Cancer

Abstract

Recurrent breast cancer occurring after the initial treatment is associated with poor outcome. A bimodal relapse pattern after surgery for primary tumor has been described with peaks of early and late recurrence occurring at about 2 and 5 years, respectively. Although several clinical and pathological features have been used to discriminate between low- and high-risk patients, the identification of molecular biomarkers with prognostic value remains an unmet need in the current management of breast cancer. Using microarray-based technology, we have performed a microRNA expression analysis in 71 primary breast tumors from patients that either remained disease-free at 5 years post-surgery (group A) or developed early (group B) or late (group C) recurrence. Unsupervised hierarchical clustering of microRNA expression data segregated tumors in two groups, mainly corresponding to patients with early recurrence and those with no recurrence. Microarray data analysis and RT-qPCR validation led to the identification of a set of 5 microRNAs (the 5-miRNA signature) differentially expressed between these two groups: miR-149, miR-10a, miR-20b, miR-30a-3p and miR-342-5p. All five microRNAs were down-regulated in tumors from patients with early recurrence. We show here that the 5-miRNA signature defines a high-risk group of patients with shorter relapse-free survival and has predictive value to discriminate non-relapsing versus early-relapsing patients (AUC = 0.993, p-value<0.05). Network analysis based on miRNA-target interactions curated by public databases suggests that down-regulation of the 5-miRNA signature in the subset of early-relapsing tumors would result in an overall increased proliferative and angiogenic capacity. In summary, we have identified a set of recurrence-related microRNAs with potential prognostic value to identify patients who will likely develop metastasis early after primary breast surgery.

Epigenetic Regulation of miRNAs and Breast Cancer Stem Cells

“…It has been observed that miR-149, miR-10a, miR-20b, miR-30a-3p and miR-342-5p were downregulated in tumors from patients who had early recurrence compared to the patients with no recurrence. These data confirmed the potential role of miRNAs to be used as prognostic markers for the different types and status of breast tumors [25]. Furthermore, it has been shown that miRNA dysregulation is an early event in breast cancer since DCIS lesions also possess dysregulated miRNA expression [27].…”

Basal-like breast cancer: molecular profiles, clinical features and survival outcomes

“…In line with our findings, these results contain additional information for the better understanding of basal-like subgroups. Additionally, high levels of hsa-miR-342-5p [72, 73] and -34a [74, 75] have been correlated to breast cancer decreased recurrence and increased survival; whereas low levels have been associated with cell death inhibition and therapy resistance. The hsa-miR-22 [76, 77] and members of the hsa-miR-29 family (-29a, -29b and -29c) [55, 78] – previously identified as tumour suppressors – have also been implicated in increased survival [78] and pointed out as promising prognostic biomarkers [77, 79].…”

Serum level of miR-10-5p as a prognostic biomarker for acute myeloid leukemia

“…We then investigated the possibility of prognostic serum miR-10a-5p marker in AML, and our results indicated that patients with up-regulated miR-10a-5p expression had a significantly shortened OS than those with a decrease in miR-10a-5p expression, which implied that expression of miR-10a-5p has an important value in AML prognosis classification. Pérez et al [38] identified that recurrence-related miR-10a-5p had potential predictive value to identify patients who will likely develop metastasis early after primary breast surgery and define a high-risk group of patients with shorter relapse-free survival. Many studies further confirmed that miR-10a-5p-repressible target genes involved in BAX/BIM/PTEN/ KLF4/CDK4 which were tumor suppressor genes closely related to the drug resistance and the previously mentioned HOX gene [39][40][41].…”