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There is current evidence implicating the Wnt/β-catenin/TCF pathway in breast cancer. We investigated the effect of para- and meta-positional isomers of nitric oxide-releasing aspirin (NO-ASA), and aspirin (ASA) on MCF-7 human breast cancer cell growth and β-catenin/TCF signaling. The p- and m-NO-ASA isomers strongly inhibited cell growth and β-catenin/TCF transcriptional activity compared to ASA; the IC50s for growth inhibition were 57 ± 4, 193 ± 10 and >5000 μM, and for transcriptional inhibition they were 12 ± 1.8, 75 ± 6.5 and >5000 μM for p-, m-NO-ASA and ASA, respectively. p-NO-ASA reduced the expression of Wnt/β-catenin downstream target gene cyclin D1, and total cellular β-catenin levels. COX-2 expression was induced by p-NO-ASA, protein kinase C inhibitors reversed this induction. p-NO-ASA blocked the cell cycle transition at S to G2/M phase. These studies suggest a targeted chemopreventive/chemotherapeutic potential for NO-ASA against breast cancer.