Levels of miR-126 and miR-218 are elevated in ductal carcinoma in situ (DCIS) and inhibit malignant potential of DCIS derived cells
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Stefano Volinia1,2,*, Valeria Bertagnolo1,*, Silvia Grassilli1, Federica Brugnoli1, Marco Manfrini1, Marco Galasso1, Cristian Scatena3, Chiara Maria Mazzanti4, Francesca Lessi4, Giuseppe Naccarato3, Adelaide Caligo3, Enzo Bianchini5, Quirino Piubello6, Enrico Orvieto7, Massimo Rugge7, Cristina Natali8, Domenico Reale8, Andrea Vecchione9, Sarah Warner10, Carlo Maria Croce10 and Silvano Capitani1,2
1Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy
2LTTA Centre, University of Ferrara, Ferrara 44121, Italy
3Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56126, Italy
4Pisa Science Foundation, Pisa 56121, Italy
5Pathology Division, S. Anna University Hospital, Ferrara 44124, Italy
6Department of Diagnostic and Pathology, Azienda Ospedaliera Universitaria Integrata di Verona, Verona 37126, Italy
7Department of Medicine DIMED, University of Padova, Padova 35121, Italy
8Pathology Division, Santa Maria della Misericordia Hospital, Rovigo 45100, Italy
9Department of Pathology, St. Andrea University Hospital, University of Rome, La Sapienza, Rome 00185, Italy
10Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
*These authors contributed equally to this work
Stefano Volinia, email: [email protected]
Valeria Bertagnolo, email: [email protected]
Keywords: DCIS; breast tumor progression; EMT; breast cancer; over-diagnosis
Received: November 28, 2017 Accepted: April 06, 2018 Published: May 04, 2018
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.
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