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Article

Circulating miRNAs in Untreated Breast Cancer: An Exploratory Multimodality Morpho-Functional Study

1
IRCCS SDN, 80143 Naples, Italy
2
Department of Advanced Biomedical Sciences, Federico II University, 80131 Naples, Italy
3
Department of Motor Sciences & Wellness, University of Naples Parthenope, 80133 Naples, Italy
4
Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(6), 876; https://doi.org/10.3390/cancers11060876
Received: 24 May 2019 / Revised: 17 June 2019 / Accepted: 20 June 2019 / Published: 22 June 2019
(This article belongs to the Special Issue Role of Medical Imaging in Cancers)
The aim of this study was to identify new disease-related circulating miRNAs with high diagnostic accuracy for breast cancer (BC) and to correlate their deregulation with the morpho-functional characteristics of the tumour, as assessed in vivo by positron emission tomography/magnetic resonance (PET/MR) imaging. A total of 77 untreated female BC patients underwent same-day PET/MR and blood collection, and 78 healthy donors were recruited as negative controls. The expression profile of 84 human miRNAs was screened by using miRNA PCR arrays and validated by real-time PCR. The validated miRNAs were correlated with the quantitative imaging parameters extracted from the primary BC samples. Circulating miR-125b-5p and miR-143-3p were upregulated in BC plasma and able to discriminate BC patients from healthy subjects (miR-125-5p area under the receiver operating characteristic ROC curve (AUC) = 0.85 and miR-143-3p AUC = 0.80). Circulating CA15-3, a soluble form of the transmembrane glycoprotein Mucin 1 (MUC-1) that is upregulated in epithelial cancer cells of different origins, was combined with miR-125b-5p and improved the diagnostic accuracy from 70% (CA15-3 alone) to 89% (CA15-3 plus miR-125b-5p). MiR-143-3p showed a strong and significant correlation with the stage of the disease, apparent diffusion coefficient (ADCmean), reverse efflux volume transfer constant (Kepmean) and maximum standardized uptake value (SUVmax), and it might represent a biomarker of tumour aggressiveness. Similarly, miR-125b-5p was correlated with stage and grade 2 but inversely correlated with the forward volume transfer constant (Ktransmean) and proliferation index (Ki67), suggesting a potential role as a biomarker of a relatively more favourable prognosis. In situ hybridization (ISH) experiments revealed that miR-143-3p was expressed in endothelial tumour cells, miR-125-5p in cancer-associated fibroblasts, and neither in epithelial tumour cells. Our results suggested that miR-125-5p and miR-143-3p are potential biomarkers for the risk stratification of BC, and Kaplan-Maier plots confirmed this hypothesis. In addition, the combined use of miR-125-b-5p and CA15-3 enhanced the diagnostic accuracy up to 89%. This is the first study that correlates circulating miRNAs with in vivo quantified tumour biology through PET/MR biomarkers. This integration elucidates the link between the plasmatic increase in these two potential circulating biomarkers and the biology of untreated BC. In conclusion, while miR-143-3b and miR-125b-5p provide valuable information for prognosis, a combination of miR-125b-5p with the tumour marker CA15-3 improves sensitivity for BC detection, which warrants consideration by further validation studies. View Full-Text
Keywords: circulating miRNAs; breast cancer; imaging parameters; PET/MRI; biomarkers circulating miRNAs; breast cancer; imaging parameters; PET/MRI; biomarkers
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MDPI and ACS Style

Incoronato, M.; Grimaldi, A.M.; Mirabelli, P.; Cavaliere, C.; Parente, C.A.; Franzese, M.; Staibano, S.; Ilardi, G.; Russo, D.; Soricelli, A.; Catalano, O.A.; Salvatore, M. Circulating miRNAs in Untreated Breast Cancer: An Exploratory Multimodality Morpho-Functional Study. Cancers 2019, 11, 876. https://doi.org/10.3390/cancers11060876

AMA Style

Incoronato M, Grimaldi AM, Mirabelli P, Cavaliere C, Parente CA, Franzese M, Staibano S, Ilardi G, Russo D, Soricelli A, Catalano OA, Salvatore M. Circulating miRNAs in Untreated Breast Cancer: An Exploratory Multimodality Morpho-Functional Study. Cancers. 2019; 11(6):876. https://doi.org/10.3390/cancers11060876

Chicago/Turabian Style

Incoronato, Mariarosaria, Anna M. Grimaldi, Peppino Mirabelli, Carlo Cavaliere, Chiara A. Parente, Monica Franzese, Stefania Staibano, Gennaro Ilardi, Daniela Russo, Andrea Soricelli, Onofrio A. Catalano, and Marco Salvatore. 2019. "Circulating miRNAs in Untreated Breast Cancer: An Exploratory Multimodality Morpho-Functional Study" Cancers 11, no. 6: 876. https://doi.org/10.3390/cancers11060876

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