Abstract
In this study, we compared the blood serum levels of circulating cell-free and exosomal microRNAs, and their involvement in the molecular subtypes of breast cancer patients. Our analyses on cell-free miR-101, miR-372 and miR-373 were performed in preoperative blood serum of 168 patients with invasive breast cancer, 19 patients with benign breast diseases and 28 healthy women. MicroRNAs were additionally quantified in exosomes of 50 cancer patients and 12 healthy women from the same cohort. Relative concentrations were measured by quantitative TaqMan MicroRNA assays and correlated to clinicopathological risk factors. The concentrations of cell-free miR-101 (p=0.013) and miR-373 (p=0.024) were significantly different between patients with breast cancer and benign tumors. A prevalence of miR-101, miR-372 and miR-373 were found in exosomes. The levels of circulating exosomal (but not cell-free) miR-373 were higher in triple negative than luminal carcinomas (p=0.027). Also, estrogen-negative (p=0.021) and progesterone-negative (p=0.01) tumors displayed higher concentrations of exosomal miR-373 than patients with hormone-receptor positive tumors. Overexpression of miR-373 by transfection of MCF-7 cells showed downregulated protein expression of the estrogen receptor, and inhibition of apoptosis induced by camptothecin. Our data indicate that serum levels of exosomal miR-373 are linked to triple negative and more aggressive breast carcinomas.
Highlights
Profiling by immunohistochemical assays using estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) classifies breast cancer into four phenotypically distinct subtypes: luminal A, luminal B, basal-like and HER2+ tumors
It was surprising to detect the different regulation of miR371, miR-372 and miR-373 that are located in the same cluster on the chromosomal region of 19q13.42
In the present study we demonstrate that in breast cancer patients and healthy women the relative exosomal serum concentrations of miR-101, miR-372 and miR-373 were usually higher than their cell-free levels, indicating that these miRs may predominantly circulate in exosomes in the peripheral blood
Summary
Profiling by immunohistochemical assays using estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) classifies breast cancer into four phenotypically distinct subtypes: luminal A, luminal B, basal-like and HER2+ tumors. The luminal A subtype is ER+ and/or PR+ and HER2-, with low Ki-67 levels and the luminal B subtype is ER+. Basal-like tumors display an expression pattern of basal myoepithelial markers and are mainly triple negative, ER-, PR- and HER2-. They account for about 10–15% of all invasive breast cancers. The clinical behavior of basal-like and HER2+ subtypes is more aggressive than that of luminal tumors, whereas the luminal A subtype corresponds to low-proliferating tumors with a good prognosis factor [2]
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