Specific microRNA signatures in exosomes of triple-negative and HER2-positive breast cancer patients undergoing neoadjuvant therapy within the GeparSixto trial

Abstract

BackgroundThe focus of this study is to identify particular microRNA (miRNA) signatures in exosomes derived from plasma of 435 human epidermal growth factor receptor 2 (HER2)-positive and triple-negative (TN) subtypes of breast cancer (BC).MethodsFirst, miRNA expression profiles were determined in exosomes derived from the plasma of 15 TNBC patients before neoadjuvant therapy using a quantitative TaqMan real-time PCR-based microRNA array card containing 384 different miRNAs. Forty-five miRNAs associated with different clinical parameters were then selected and mounted on microRNA array cards that served for the quantification of exosomal miRNAs in 435 BC patients before therapy and 20 healthy women. Confocal microscopy, Western blot, and ELISA were used for exosome characterization.ResultsQuantification of 45 exosomal miRNAs showed that compared with healthy women, 10 miRNAs in the entire cohort of BC patients, 13 in the subgroup of 211 HER2-positive BC, and 17 in the subgroup of 224 TNBC were significantly deregulated. Plasma levels of 18 exosomal miRNAs differed between HER2-positive and TNBC subtypes, and 9 miRNAs of them also differed from healthy women. Exosomal miRNAs were significantly associated with the clinicopathological and risk factors. In uni- and multivariate models, miR-155 (p = 0.002, p = 0.003, respectively) and miR-301 (p = 0.002, p = 0.001, respectively) best predicted pathological complete response (pCR).ConclusionOur findings show a network of deregulated exosomal miRNAs with specific expression patterns in exosomes of HER2-positive and TNBC patients that are also associated with clinicopathological parameters and pCR within each BC subtype.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1163-y) contains supplementary material, which is available to authorized users.

The role of exosomal microRNAs; focus on clinical applications in breast cancer

“…Differential expressions of subtype-specific miRNAs have also been reported in several studies [27,37] . Eichelser et al [27] analyzed circulating cell-free and exosomal miR-101, miR-372, and miR-373 in preoperative blood serum.…”

“…There have been few studies concerning the association between exosomal miRNAs and treatment efficacy in the clinical setting. We found one article by Stevic et al [37] on this topic. They analyzed several exosomal miRNAs which were determined based on analysis with a microRNA array card using the patients' plasma samples before neoadjuvant therapy (GeparSixto trial).…”

“…Moreover, the levels of circulating exosomal miR-373 were higher in receptor-negative and TN tumors than in hormone receptor-positive carcinomas or healthy controls. In addition, Stevic et al [37] also demonstrated different exosomal miRNA signatures in HER2-positive and TN breast cancer patients. The expression levels of exosomal miRNA in plasma of 435 breast cancer patients, consisting of 211 HER2positive and 224 TN patients, were analyzed.…”

Systematic characterization of non‐coding RNAs in triple‐negative breast cancer

“…Moreover, exosomal miRNAs could serve as monitoring indicators for therapeutic response. Stevic et al 68 found that 17 miRNAs in 224 TNBC patients who underwent neoadjuvant therapy were significantly deregulated, which were significantly associated with the clinic‐pathological and risk factors. To sum up, as a novel hotspot of cancer research, exosome‐mediated miRNAs may act as multiple roles in TNBC, which should be further explored in the future.…”

Identification of exosomal miR-455-5p and miR-1255a as therapeutic targets for breast cancer

“…There also several studies to investigate the exosomal miRNA expression profiles in order to screen crucial exosomal miRNAs for breast cancer progression. However, most of them focused on chemoresistance mechanisms in breast cancer cells [14,15] or biomarker screening in serum or plasma of patients [16][17][18]. In the present study, we aimed to identify exosomal differentially expressed miRNAs (DEMs) between breast cancer cells and normal control cells by comprehensive analysis of two microarray datasets downloaded from the public Gene Expression Omnibus (GEO) database.…”