Abstract
BackgroundMicroRNAs (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.MethodsSpecimens 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.ResultsOn 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.ConclusionsmiRNA 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.
Highlights
MicroRNAs are promising biomarkers due to their structural stability and distinct expres‐ sion profile in various cancers
Patient and tumor characteristics The women included in the Norwegian Women and Cancer study (NOWAC) study are all born in the period 1943–1957
MiRNA expression levels in malignant versus normal breast tissue Of a total of 108 cases of invasive breast cancer cases in this pilot study, five specimens did not have satisfactory RNA quality and were not included in the microarray, and one specimen was identified as an extreme outlier in the unsupervised analyses of the miRNA results using
Summary
MicroRNAs (miRNAs) are promising biomarkers due to their structural stability and distinct expres‐ sion profile in various cancers. Approximately 2.09 million women worldwide are diagnosed with breast cancer whereas an estimated 627.000 women die of the disease [1]. There is a need for simple, safe and informative diagnostic tools to better identify the breast cancer tumors with the most aggressive behavior and to diagnose and treat the disease before distant metastases have been established and the disease is beyond curability. MiRNAs have properties that make them promising as biomarkers. They can be detected in blood, partly in extracellular vesicles known as exosomes, and in other body fluids such as urine and saliva [7, 8]. If miRNAs in blood could give information on the phenotype or aggressiveness of a given tumor, there is a possibility that obtained samples could give information on malignant disease, both at the time of primary diagnosis and in the metastatic setting [10]
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