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Levels of miR-126 and miR-218 are elevated in ductal carcinoma in situ (DCIS) and inhibit malignant potential of DCIS derived cells

2018; Impact Journals LLC; Volume: 9; Issue: 34 Linguagem: Inglês

10.18632/oncotarget.25261

1949-2553

Stefano Volinia, Valeria Bertagnolo, Silvia Grassilli, Federica Brugnoli, Marco Manfrini, Marco Galasso, Cristian Scatena, Chiara Maria Mazzanti, Francesca Lessi, Antonio Giuseppe Naccarato, Maria A. Caligo, E Bianchini, Quirino Piubello, Enrico Orvieto, Massimo Rugge, Cristina Natali, Domenico Reale, Andrea Vecchione, Sarah Warner, Carlo M. Croce, Silvano Capitani,

Cancer-related molecular mechanisms research

// Stefano Volinia 1, 2, * , Valeria Bertagnolo 1, * , Silvia Grassilli 1 , Federica Brugnoli 1 , Marco Manfrini 1 , Marco Galasso 1 , Cristian Scatena 3 , Chiara Maria Mazzanti 4 , Francesca Lessi 4 , Giuseppe Naccarato 3 , Adelaide Caligo 3 , Enzo Bianchini 5 , Quirino Piubello 6 , Enrico Orvieto 7 , Massimo Rugge 7 , Cristina Natali 8 , Domenico Reale 8 , Andrea Vecchione 9 , Sarah Warner 10 , Carlo Maria Croce 10 and Silvano Capitani 1, 2 1 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy 2 LTTA Centre, University of Ferrara, Ferrara 44121, Italy 3 Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56126, Italy 4 Pisa Science Foundation, Pisa 56121, Italy 5 Pathology Division, S. Anna University Hospital, Ferrara 44124, Italy 6 Department of Diagnostic and Pathology, Azienda Ospedaliera Universitaria Integrata di Verona, Verona 37126, Italy 7 Department of Medicine DIMED, University of Padova, Padova 35121, Italy 8 Pathology Division, Santa Maria della Misericordia Hospital, Rovigo 45100, Italy 9 Department of Pathology, St. Andrea University Hospital, University of Rome, La Sapienza, Rome 00185, Italy 10 Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA * These authors contributed equally to this work Correspondence to: Stefano Volinia, email: s.volinia@unife.it Valeria Bertagnolo, email: bgv@unife.it Keywords: DCIS; breast tumor progression; EMT; breast cancer; over-diagnosis Received: November 28, 2017 Accepted: April 06, 2018 Published: May 04, 2018 ABSTRACT A substantial number of ductal carcinoma in situ (DCIS) detected by mammography never progress to invasive ductal carcinoma (IDC) and current approaches fail to identify low-risk patients not at need of adjuvant therapies. We aimed to identify the key miRNAs protecting DCIS from malignant evolution, that may constitute markers for non-invasive lesions. We studied 100 archived DCIS samples, including pure DCIS, DCIS with adjacent IDC and pure DCIS from patients with subsequent IDC in contralateral breast or no recurrence. A DCIS derived cell line was used for molecular and cellular studies. A genome wide study revealed that pure DCIS has higher miR-126 and miR-218 expression than DCIS with adjacent IDC lesions or than IDC. The down-regulation of miR-126 and miR-218 promoted invasiveness in vitro and, in patients with pure DCIS, was associated with later onset of IDC. Survival studies of independent cohorts indicated that both miRNAs play a protective role in IDC. The clinical findings are in agreement with the miRNAs' roles in cell adhesion, differentiation and proliferation. We propose that miR-126 and miR-218 have a protective role in DCIS and represent novel biomarkers for the risk assessment in women with early detection of breast cancer.