Pri-miR526b and Pri-miR655 Are Potential Blood Biomarkers for Breast Cancer.

Mousumi Majumder,Peeyush K Lala,Sujit Maiti,Kingsley Chukwunonso Ugwuagbo,Muriel Brackstone

doi:10.3390/cancers13153838

Mousumi Majumder, Peeyush K Lala + Show 3 more

Open Access

https://doi.org/10.3390/cancers13153838

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Abstract

Simple SummaryPreviously, we reported that the expression of two oncogenic miRNAs, miR526b and miR655, in poorly metastatic breast cancer cells enhances aggressive breast cancer phenotypes. Furthermore, miR526b and miR655 expression in breast tumors is associated with poor patient survival. We recently showed that both miRNAs are major regulators of the tumor microenvironment and can be detected in cell-free tumor cell secretions. Therefore, we wanted to test the biomarker potential of these two miRNAs. Early detection can improve breast cancer patient survival by 98%. Here, we report novel findings that precursors of both miRNAs, pri-miR526b and pri-miR655, are sensitive and robust blood biomarkers to distinguish cancer from benign plasmas. Pri-miR526b proved to be a very sensitive biomarker in detecting breast cancer at an early stage. Hence, pri-miR526b can be used as an early diagnostic biomarker for breast cancer.We reported that two microRNAs, miR526b and miR655, are oncogenic in breast cancer (BC). Overexpression of these two miRNAs in poorly metastatic BC cells promotes aggressive BC phenotypes in vitro and in vivo. High expression of each miRNA was associated with poor patient survival. In this pilot biomarker study, we report for the first time that miRNA precursor RNAs (pri-miRNAs) are robust and sensitive biomarkers for BC, detectable in both human blood plasma and biopsy tissues. Pri-miRNA detection and quantification do not require a special enrichment procedure, thus reducing specimen quantity. Blood plasma samples from 90 malignant tumor-bearing patients and 20 benign lesion-bearing participants (control) were analyzed for pri-miRNA expression with a quantitative real-time polymerase chain reaction. Results revealed that normalized expressions of plasma pri-miR526b and pri-miR655 are significantly upregulated in malignancy compared to benign plasmas (p = 0.002 and p = 0.03, respectively). Both pri-miRNAs showed more prominent results to distinguish stage I plasmas from benign plasmas (p = 0.001 for pri-miR526b and p = 0.0001 for pri-miR655). We have also validated pri-miRNA expression in independent tumor bank tissues, showing significant upregulation of both pri-miRNAs in BC; thus, pri-miRNAs are robust markers. The diagnostic relevance of pri-miRNAs was computed with the area under the curve (AUC). Pri-miR526b is a sensitive biomarker to distinguish cancer from control plasmas (sensitivity of 86%; AUC = 71.47%, p = 0.0027) with a positive predictive value of 88.89%; however, pri-miR655 did not show significant sensitivity. Furthermore, pri-miR526b could also significantly distinguish tumors as early as stage I from control (sensitivity of 75%; AUC = 72.71%, p = 0.0037). Therefore, pri-miR526b can be used as an early diagnostic biomarker. The expression of both pri-miRNAs was significantly high in ER-positive and HER2-negative subgroups of BC; hence, these biomarkers might play a role in the management of endocrine therapy designs. Additionally, with a case–control cohort study, we identified that high expression of pri-miR526b in the blood is also a risk factor associated with breast cancer (OR = 4.3, CI = 1.39–13.34, p = 0.01). Pri-miRNAs could be considered novel breast cancer blood biomarkers.

Highlights

Breast cancer (BC) is the most common solid organ-specific cancer, affecting about30–40% of women under the age of 40 years in North America [1]
The blood plasma of the control subjects was collected from benign tumor-bearing individuals or nontumor lesions at the London Tumor Biobank (LTB)
We have shown that these two miRNAs can be found in the cell-free conditioned media of miRNA-overexpressing cell lines [19] and these miRNAs can change the tumor microenvironment (TME) and enhance tumor-associated angiogenesis [20], hypoxia [21], and oxidative stress [19] in breast cancer

Summary

Introduction

Breast cancer (BC) is the most common solid organ-specific cancer, affecting about30–40% of women under the age of 40 years in North America [1]. Mammographic screening is a painful breast examination procedure, currently used as the gold standard for tumor detection This screening excludes women below the age of 50 years in Canada [4] and is limited by a high percentage of false positive results, which requires further investigation for molecular signatures using invasive biopsy techniques [5]. A blood test can be a less invasive procedure for BC screening, and there are a few routine cancer markers in the blood, such as carcinoembryonic antigen (CEA) and carbohydrate antigen (CA), which have been used as biomarkers Their low sensitivity and specificity to detect disease make them poorly reliable screening tools [6]. The identification of microRNAs (miRNAs) in body fluids and in the blood make them strong candidates as cancer biomarkers [7]

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