gsk2830371 and Breast-Neoplasms

Cancer can metastasize from early lesions without detectable tumors. Despite extensive studies on metastasis in cancer cells from patients with detectable primary tumors, mechanisms for early metastatic dissemination are poorly understood. Her2 promotes breast cancer early dissemination by inhibiting p38, but the downstream pathway in this process was unknown. Using early lesion breast cancer models, we demonstrate that the effect of p38 suppression by Her2 on early dissemination is mediated by MK2 and heat shock protein 27 (Hsp27). The early disseminating cells in the MMTV-Her2 breast cancer model are Her2

Topics: Aminopyridines; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Dipeptides; Female; Heat-Shock Proteins; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Intracellular Signaling Peptides and Proteins; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase 14; Molecular Chaperones; Neoplasm Metastasis; Phosphorylation; Protein Phosphatase 2C; Protein Serine-Threonine Kinases; Pyridines; Receptor, ErbB-2; Xenograft Model Antitumor Assays

PP2C family serine/threonine phosphatase WIP1 acts as a negative regulator of the tumor suppressor p53 and is implicated in silencing of cellular responses to genotoxic stress. Chromosomal locus 17q23 carrying the PPM1D (coding for WIP1) is commonly amplified in breast carcinomas and WIP1 was proposed as potential pharmacological target. Here we employed a cellular model with knocked out PPM1D to validate the specificity and efficiency of GSK2830371, novel small molecule inhibitor of WIP1. We have found that GSK2830371 increased activation of the DNA damage response pathway to a comparable level as the loss of PPM1D. In addition, GSK2830371 did not affect proliferation of cells lacking PPM1D but significantly supressed proliferation of breast cancer cells with amplified PPM1D. Over time cells treated with GSK2830371 accumulated in G1 and G2 phases of the cell cycle in a p21-dependent manner and were prone to induction of senescence by a low dose of MDM2 antagonist nutlin-3. In addition, combined treatment with GSK2830371 and doxorubicin or nutlin-3 potentiated cell death through a strong induction of p53 pathway and activation of caspase 9. We conclude that efficient inhibition of WIP1 by GSK2830371 sensitizes breast cancer cells with amplified PPM1D and wild type p53 to chemotherapy.

Topics: Aminopyridines; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Proliferation; Dipeptides; DNA Damage; Drug Resistance, Neoplasm; Female; Humans; Imidazoles; Piperazines; Protein Phosphatase 2C; Proto-Oncogene Proteins c-mdm2; Tumor Cells, Cultured; Tumor Suppressor Protein p53