Differential expression of the miR-17-92 cluster and miR-17 family in breast cancer according to tumor type; results from the Norwegian Women and Cancer (NOWAC) study

Abstract

Background MicroRNAs (miRNAs) are promising biomarkers due to their structural stability and distinct expression profile in various cancers. We wanted to explore the miRNA expression in benign breast tissue and breast cancer subgroups in the Norwegian Women and Cancer study. Methods Specimens and histopathological data from study participants in Northern Norway diagnosed with breast cancer, and benign tissue from breast reduction surgery were collected. Main molecular subtypes were based on surrogate markers; luminal A (ER+ and/or PR+, HER2− and Ki67 ≤ 30%), luminal B (ER+ and/or PR+, HER2− and Ki67 > 30% or ER+ and/or PR+ and HER2+), HER2 positive (ER− and PR− and HER2+) and triple-negative (ER−, PR− and HER2−). RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue, and miRNAs were successfully analyzed in 102 cancers and 36 benign controls using the 7th generation miRCURY LNA microarray containing probes targeting all human miRNAs as annotated in miRBASE version 19.0. Validation with RT-qPCR was performed. Results On average, 450 miRNAs were detected in each sample, and 304 miRNAs were significantly different between malignant and benign tissue. Subgroup analyses of cancer cases revealed 23 miRNAs significantly different between ER+ and ER− tumors, and 47 miRNAs different between tumors stratified according to grade. Significantly higher levels were found in high grade tumors for miR-17-5p (p = 0.006), miR-20a-5p (p = 0.007), miR-106b-5p (p = 0.007), miR-93-5p (p = 0.007) and miR-25-3p (p = 0.015) from the paralogous clusters miR-17-92 and miR-106b-25. Expression of miR-17-5p (p = 0.0029), miR-20a-5p (p = 0.0021), miR-92a-3p (p = 0.011) and miR-106b-5p (p = 0.021) was significantly higher in triple-negative tumors compared to the rest, and miR-17-5p and miR-20a-5p were significantly lower in luminal A tumors. Conclusions miRNA expression profiles were significantly different between malignant and benign tissue and between cancer subgroups according to ER− status, grade and molecular subtype. miRNAs in the miR-17-92 cluster and miR-17 family were overexpressed in high grade and triple-negative tumors associated with aggressive behavior. The expression and functional role of these miRNAs should be further studied in breast cancer to explore their potential as biomarkers in diagnostic pathology and clinical oncology.

High-metastatic cancer cells derived exosomal miR92a-3p promotes epithelial-mesenchymal transition and metastasis of low-metastatic cancer cells by regulating PTEN/Akt pathway in hepatocellular carcinoma

“…For instance, miR92a-3p is secreted by tumor cells and stimulates tumor-associated macrophages to produce IL6, a pro-inflammatory cytokine, subsequently promoting the progression of liposarcoma [ 35 ]. MiR92a-3p also plays its oncogenic role in gastric cancer [ 36 ], colorectal cancer [ 37 ] and breast cancer [ 38 ]. However, miR92a-3p may have other roles in cancers.…”

microRNA Expression Profile in Single Hormone Receptor-Positive Breast Cancers Is Mainly Dependent on HER2 Status—A Pilot Study

“…Its associations with ERα are unclear, but it directly downregulates ERβ in breast cancer [31]. In the Norwegian Women and Cancer study, miR-92a-3p was upregulated in triple-negative carcinomas [32]. So far, few studies have investigated interactions between PgR and miRNAs.…”

Model-Based Integration Analysis Revealed Presence of Novel Prognostic miRNA Targets and Important Cancer Driver Genes in Triple-Negative Breast Cancers

“…Another characteristic of these miRNAs is the formation of clusters in various cancers and their acting as modulators for important cell functions. It has been noted that these clusters usually reside very near to the known cancerous sites or genomics hotspots and play a very important role in carcinogenesis [59,60]. We identified two members of the miRNA let family hsa-let-7c/b targeting KRT5 and GABBR2, involved in molecular functions such as G-protein-coupled signaling, protein binding and structural activity.…”