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Title: Role of miRNAs in the tumour-mediated vascularisation of triple negative breast cancer
Author: D'Ippolito, Elvira
ISNI:       0000 0004 5991 953X
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2016
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Neoplastic cells of aggressive tumours can differentiate into endothelial-like cells acquiring the expression of endothelial markers (e.g. CD31) and the ability to participate in the establishment of the tumour vasculature. These tumour-mediated vascular structures promote cancer progression and their presence associates with poor outcome. In triple negative breast cancer (TNBC), we identified platelet-derived growth factor receptor beta (PDGFRP) as an important player of this process. Interestingly, PDGFRp is a promising target in breast cancer; however, therapies with multi-target tyrosine-kinase inhibitors against this receptor have been disappointing. Thus, we aimed at investigating the role of microRNAs (miRNAs) as targets or drugs for the modulation of PDGFRp-mediated vasculogenic properties of TNBC, focusing on miR-9 and miR-200 family. We showed that miR-9 and mir-200 promoted and inhibited, respectively, the in vitro formation of vascular-like structures (loops) in MDA-MB-231 and MDA-MB-157 TNBC cell lines. MiR-9 was induced upon PDGFR~ activation and mediated loop formation ability partially through the direct targeting of STARD13. Mir-200, instead, indirectly suppressed PDGFRp by the inhibition of ZEB1. To confirm these effects in vivo, we generated MDA-MB-231 xenografted mice models for either the stable modulation of miRNAs or the peritumoural delivery of miRNA-based drugs. Notably, both miR-9 inhibition and miR-200c restoration strongly decreased the number of tumour-derived vascular lacunae, identified as vascular-like structures lined by CD31-positive tumour cells. Finally, in TNBC specimens, immunohistochemistry and immunofluorescence analyses indicated that PDGFRp identified tumour cells engaged in vascular lacunae. Interestingly, the presence of PDGFRp-positive structures negatively associated with miR-200c expression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available