Can the microRNA expression profile help to identify novel targets for zoledronic acid in breast cancer?
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Daniele Fanale1,*, Valeria Amodeo1,*, Viviana Bazan1,*, Lavinia Insalaco1, Lorena Incorvaia1, Nadia Barraco1, Marta Castiglia1, Sergio Rizzo1, Daniele Santini2, Antonio Giordano3, Sergio Castorina4,5,#, Antonio Russo1,#
1Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
2University Campus Bio-Medico, Department of Medical Oncology, Rome, Italy
3Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
4Fondazione Mediterranea “G.B. Morgagni”, Catania, Italy
5Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
#Co-last authors, these authors contributed equally to this work
*These authors contributed equally to this work
Antonio Russo, e-mail: [email protected]
Keywords: bone metastasis, breast cancer, microarray analysis, miRNA expression profile, zoledronic acid
Received: March 08, 2016 Accepted: March 31, 2016 Published: April 13, 2016
Zoledronic acid (ZOL), belonging to third generation bisphosphonate family, is a potent inhibitor of osteoclast-mediated bone resorption, widely used to effectively prevent osteolysis in breast cancer patients who develop bone metastases. Low doses of ZOL have been shown to exhibit a direct anticancer role, by inhibiting cell adhesion, invasion, cytoskeleton remodelling and proliferation in MCF-7 breast cancer cells. In order to identify the molecular mechanisms and signaling pathways underlying the anticancer activity exerted by ZOL, we analyzed for the first time the microRNA expression profile in breast cancer cells. A large-scale microarray analysis of 377 miRNAs was performed on MCF7 cells treated with 10 μM ZOL for 24 h compared to untreated cells. Furthermore, the expression of specific ZOL-induced miRNAs was analyzed in MCF-7 and SkBr3 cells through Real-time PCR. Low-dose treatment with ZOL significantly altered expression of 54 miRNAs. Nine upregulated and twelve downregulated miRNAs have been identified after 24 h of treatment. Also, ZOL induced expression of 11 specific miRNAs and silenced expression of 22 miRNAs. MiRNA data analysis revealed the involvement of differentially expressed miRNAs in PI3K/Akt, MAPK, Wnt, TGF-β, Jak-STAT and mTOR signaling pathways, and regulation of actin cytoskeleton. Our results have been shown to be perfectly coherent with the recent findings reported in literature concerning changes in expression of some miRNAs involved in bone metastasis formation, progression, therapy resistance in breast cancer. In conclusion, this data supports the hypothesis that ZOL-induced modification of the miRNA expression profile contributes to the anticancer efficacy of this agent.
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