Author(s): Xiaomeng Cui (1,2), Zhangming Li (3), Yilei Zhao (4), Anqi Song (5), Yunbo Shi (1,2), Xin Hai (4), Wenliang Zhu (6)
Breast cancer (BC) is one of the most common cancers that accounts for one in four diagnosed cancers and affects one in eight females worldwide (Torre et al., 2015). Approximately 1.5 million new BC cases are reported per year (Siegel, Miller & Jemal, 2015), which is close to the existing 1.7 million BC cases reported in 2012. Conservative estimates suggested higher morbidity rates associated with BC though only prolonged life expectancy of females was considered. Therefore, early demographic screening is necessary to manage the unprecedented increase in the malignant disease (Myers et al., 2015). However, currently employed BC screening methods have relatively low sensitivity and insufficient identification power, leading to a high false positive rate of 20.5% in women aged 40-49years (Van den Ende et al., 2017). Therefore, there is a need for the development of novel biomarkers for early detection of BC.
MicroRNAs (miRNAs) are a class of single-stranded small non-coding RNA molecules of ~22 nucleotides. miRNAs act as post-transcriptional gene expression regulators via complementary binding to the 3'-untranslated regions of mRNAs (Bartel, 2009). Recent studies have shown important involvement of miRNAs in the pathological process of BC via regulating proliferation and energy synthesis of BC cells (Li et al., 2017; Chen et al., 2018; Xiao et al., 2018). The miRBase database currently includes data on more than 2,800 mature human miRNAs (Kozomara & Griffiths-Jones, 2014). Of these, some miRNAs, such as miR-21 and miR-155, have demonstrated potential value for the early diagnosis of BC (Hamam et al., 2017). Meanwhile, the development of new detection techniques made accurate detection of low-abundance circulating miRNAs no longer an obstacle (Majd, Salimi & Ghasemi, 2018).
Despite significant progress in research on the use of circulating miRNAs as diagnostic BC biomarkers, one major limitation is that most studies have small sample sizes, which results in poor inter-study reproducibility (Nassar, Nasr & Talhouk, 2017). Thus, there is a need for a systematic review of candidate biomarkers reported in previous clinical studies. BC is considered a collection of mammary gland-related heterogeneous diseases (Bertos & Park, 2011). In addition, the high BC prevalence requires large sample sizes so that multiple types of BC can be investigated in a single circulating miRNA biomarker study. So far, only one study has met this requirement. In a study comprising approximately 4,000 patients and healthy subjects, Shimomura and his colleagues performed a microarray-based circulating miRNA biomarker assay for early detection of BC in the Japanese population (Shimomura et al., 2016). The authors validated the effectiveness of a biomarker panel comprising five miRNAs (miR-1246, miR-1307-3p, miR-4634, miR-6861-5p, and miR-6875-5p) for BC diagnosis with 89.7% accuracy. Surprisingly, the aforementioned five miRNAs were not reported by other studies with small sample sizes (Nassar, Nasr & Talhouk, 2017). Therefore, larger sample sizes can facilitate the discovery of miRNA biomarkers, while smaller sample sizes can introduce more sampling error and inconsistencies in...