Research objectives. The objectives of this research were to elucidate the underlying mechanisms that link aberrant PP2Cδ levels with breast cancer development. A prespecified hypothesis was that PP2Cδ impairs p53 acetylation and DDR by compromising BRCA1 function. Once we confirmed the cross-talk between PP2Cδ and BRCA1/p300-p53 pathway, we investigated the clinical IHC data to explore the relationships between PP2Cδ levels and BRCA1 phosphorylation or p53 acetylation in human breast cancer specimens, as well as the correlation with patients’ histological grade. Furthermore, we sought to evaluate whether inhibition of PP2Cδ with C23, our newly developed PP2Cδ inhibitor, would potentiate the antineoplastic effects of Dox in MCF-7 xenograft–bearing nude mice.

Ethics statement. All animal studies were performed in accordance with the guidelines approved by the Institutional Animal Care and Use Committee of Charles R. Drew University of Medicine and Science.

Study design. To explore the molecular mechanisms underlying PP2Cδ inhibition of p53 acetylation, genetic ablation, or chemical inhibition, single base mutation, deletion mutation, and gene overexpression techniques were used. To evaluate whether inhibition of PP2Cδ would potentiate the antineoplastic effects of Dox, MCF-7 xenograft–bearing nude mice were used in these studies. We designed the studies to test the different agents with 10 mice per treatment group (one xenograft per mouse). Mice were randomized on the basis of tumor volume. With 10 mice per group, an effect size of 1.3 with 80% power could be detected, which was reasonable for a controlled animal experiment. The drugs used were coded so that researchers did not know which drug or combination treatments were used until experiments and analysis are completed.

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