Analysis of molecular mechanisms and anti-tumoral effects of zoledronic acid in breast cancer cells

Background: Zoledronic acid (ZOL) is the most potent nitrogen-containing bisphosphonate (N-BPs) that strongly binds to bone mineral and acts as a powerful inhibitor of bone resorption, already clinically available for the treatment of patients with osteolytic metastases. Recent data also suggest that ZOL, used in breast cancer, may provide more than just supportive care modifying the course of the disease, though the possible molecular mechanism of action is still unclear. Aims: Since breast cancer is one of the primary tumors with high propensity to metastasize to the bone, we investigated, for the first time, differential gene expression profile on MCF-7 breast cancer cells treated with low doses of ZOL (10μM). Materials and Methods: Microarrays analysis was used to identify, describe and summarize evidences regarding the molecular basis of actions of ZOL and of their possible direct anti-tumor effects. We validated gene expression results of specific transcripts involved on major cellular process by Real Time and Western Blot analysis and we observed inhibition of proliferation and migration through MTT and Matrigel assay. Results: We then focused on changes in the cytoskeletal components as FN1, actin, and anti angiogenic compounds as TGF-β1 and THBS1. The upregulation of these products may have an important role in inhibiting proliferation, invasion and angiogenesis mediated by ZOL. Conclusions: In conclusion, in the present studies, we investigated the role of ZOL in the regulation of breast cancer cell invasion. Our results demonstrated that ZOL, via cytoskeletal remodelling, plays an inhibitory role in breast cancer cell invasion, possibly by specifically up-regulating the TGF- β1/Smad signaling pathway, and the downstream activity of FN1 and ACTIN.