MiR-9 and miR-200 regulate PDGFRβ-mediated endothelial differentiation of tumor cells in triple negative breast cancer

D'Ippolito, E; Plantamura, I; Bongiovanni, L; Casalini, P; Baroni, S; Piovan, C; Orlandi, R; Gualeni, A; Gloghini, A; Rossini, A; Cresta, S; Tessari, A; De Braud, F; Di Leva, Gianpiero; Tripodo, C; Iorio, M

Abstract

Organization of cancer cells into endothelial-like cell lined structures to support neovascularization and fuel solid tumors is a hallmark of progression and poor outcome. In triple negative breast cancer (TNBC), PDGFRβ has been identified as a key player of this process and is considered a promising target for breast cancer therapy. Thus, we aimed at investigating the role of microRNAs as therapeutic approach to inhibit PDGFRβ–mediated vasculogenic properties of TNBC, focusing on miR-9 and miR-200.
In MDA-MB-231 and MDA-MB-157 TNBC cell lines, miR-9 and miR-200 promoted or inhibited, respectively, the formation of vascular-like structures in vitro. Induction of endogenous miR-9 expression, upon ligand-dependent stimulation of PDGFRβ signaling, promoted significant vascular-sprouting of TNBC cells in part by direct repression of STARD13. Conversely, ectopic expression of miR-200 inhibited this sprouting by indirectly reducing the protein levels of PDGFRβ through the direct suppression of ZEB1.
Notably, in vivo miR-9 inhibition or miR-200c restoration, through either the generation of MDA- MB-231 stable clones or peritumoral delivery in MDA-MB-231 xenografted mice, strongly decreased the number of vascular lacunae. Finally, immunohistochemistry and immunofluorescence analyses in TNBC specimens indicated that PDGFRβ expression marked tumor cells engaged in vascular lacunae.
In conclusion, our results demonstrate that miR-9 and miR-200 play opposite roles in the regulation of the vasculogenic ability of TNBC, acting as facilitator and suppressor of PDGFRβ, respectively. Moreover, our data support the possibility to therapeutically exploit miR-9 and miR- 200 to inhibit the process of vascular lacunae formation in TNBC.

Citation

D'Ippolito, E., Plantamura, I., Bongiovanni, L., Casalini, P., Baroni, S., Piovan, C., …Iorio, M. (2016). MiR-9 and miR-200 regulate PDGFRβ-mediated endothelial differentiation of tumor cells in triple negative breast cancer. Cancer Research, 76(14), https://doi.org/10.1158/0008-5472.CAN-16-0140

• Journal Article Type: Article
• Acceptance Date: Jul 6, 2016
• Online Publication Date: Jul 11, 2016
• Publication Date: Sep 1, 2016
• Deposit Date: Jul 26, 2016
• Publicly Available Date: Jul 26, 2016
• Journal: Cancer Research
• Print ISSN: 0008-5472
• Electronic ISSN: 1538-7445
• Publisher: American Association for Cancer Research
• Volume: 76
• Issue: 14
• DOI: https://doi.org/10.1158/0008-5472.CAN-16-0140
• Publisher URL: http://dx.doi.org/10.1158/0008-5472.CAN-16-0140
• Related Public URLs: http://cancerres.aacrjournals.org/