Abstract
PurposeNovel noninvasive biomarkers with high sensitivity and specificity for the diagnosis of breast cancer (BC) are urgently needed in clinics. The aim of this study was to explore whether miRNAs from the miR-106a–363 cluster can be detected in the circulation of BC patients and whether these miRNAs can serve as potential diagnostic biomarkers.MethodsThe expression of 12 miRNAs from the miR-106a–363 cluster was evaluated using qRT-PCR in 400 plasma samples (from 200 BC patients and 200 healthy controls (HCs)) and 406 serum samples (from 204 BC patients and 202 HCs) via a three-phase study. The identified miRNAs were further examined in tissues (32 paired breast tissues), plasma exosomes (from 32 BC patients and 32 HCs), and serum exosomes (from 32 BC patients and 32 HCs).ResultsUpregulated levels of four plasma miRNAs (miR-106a-3p, miR-106a-5p, miR-20b-5p, and miR-92a-2-5p) and four serum miRNAs (miR-106a-5p, miR-19b-3p, miR-20b-5p, and miR-92a-3p) were identified and validated in BC. A plasma 4-miRNA panel and a serum 4-miRNA panel were constructed to discriminate BC patients from HCs. The areas under the receiver-operating characteristic curves of the plasma panel were 0.880, 0.902, and 0.858, and those of the serum panel were 0.910, 0.974, and 0.949 for the training, testing, and external validation phases, respectively. Two overlapping miRNAs (miR-106a-5p and miR-20b-5p) were consistently upregulated in BC tissues. Except for the expression of the plasma-derived exosomal miR-20b-5p, the expression patterns of exosomal miRNAs were concordant between plasma and serum, indicating the potential use of exosomal miRNAs as biomarkers.ConclusionWe identified four plasma miRNAs and four serum miRNAs from the miR-106a–363 cluster as promising novel biomarkers for the diagnosis of BC.
Highlights
Breast cancer (BC) is the most commonly diagnosed cancer in females worldwide, accounting for 29% of all new cancers among females in 2015
reverse transcription (RT) reactions were conducted at 42 °C for 60 min followed by 70 °C for 10 min, and qRT-PCR was performed at 95 °C for 20 s, followed by 40 cycles of 95 °C for 10 s, 60 °C for 20 s, and 70 °C for 10 s on a LightCycler® 480 Real-Time PCR System (Roche Diagnostics, Mannheim, Germany) in 384-well plates [27, 28]
The expression of an individual miRNA from plasma and plasma-derived exosome samples was quantified relative to the expression of the combination of cel-miR-39 and miR-16, while miRNA expression from serum and serum-derived exosome samples was determined relative to the expression of the combination of cel-miR-39 and miR-1228, RNU6B (U6) was used to determine relative expression levels of miRNAs in tissue specimens [29, 30]
Summary
Breast cancer (BC) is the most commonly diagnosed cancer in females worldwide, accounting for 29% of all new cancers among females in 2015. Improvements in the early detection of BC by mammography, ultrasound, MRI and invasive core needle biopsy have decreased death rates [3]. Mammographic screening, which is a gold standard for BC diagnosis, has deficiencies regarding the effects of ionizing radiation and decreased sensitivity for early detection due to increased breast density [4, 5]. Most diagnostic methods require a minimum tumor volume for detection, which can translate into an advanced stage at diagnosis. Some circulating tumor markers, such as carcinoembryonic antigen and carbohydrate antigen 15-3, have been used to detect BC, but the sensitivity of these markers is low [6, 7]. New sensitive, specific, and relatively noninvasive biomarkers that can facilitate the early detection of BC are urgently needed
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