The tumor suppressor p53 plays a key role in malignant transformation and tumor development. However, the frequency of p53 mutations within individual types of cancer is different, suggesting the existence of other mechanisms attenuating p53 tumor suppressor activity. Changes in upstream regulators of p53 such as MDM2 amplification and overexpression, expression of viral oncoproteins, estrogen receptor signaling, or changes in p53 transcriptional target genes were previously described in wild-type p53 tumors. We identified a novel pathway responsible for attenuation of p53 activity in human cancers. We demonstrate that AGR2, which is overexpressed in a variety of human cancers and provides a poor prognosis, up-regulates DUSP10 which subsequently inhibits p38 MAPK and prevents p53 activation by phosphorylation. Analysis of human breast cancers reveals that AGR2 specifically provides a poor prognosis in ER+ breast cancers with wild-type p53 but not ER- or mutant p53 breast cancers, and analysis of independent data sets show that DUSP10 levels also have prognostic significance in this specific sub-group of patients. These data not only reveal a novel pro-oncogenic signaling pathway mediating resistance to DNA damaging agents in human tumors, but also has implications for designing alternative strategies for modulation of wild-type p53 activity in cancer therapy.

• Keywords
• AGR2, Breast cancer, DUSP10, Drug resistance, p38 MAPK, p53,
• MeSH
• Enzyme Activation drug effects   MeSH
• Drug Resistance, Neoplasm MeSH
• Adult MeSH
• Mitogen-Activated Protein Kinase Phosphatases metabolism   MeSH
• Dual-Specificity Phosphatases metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• p38 Mitogen-Activated Protein Kinases metabolism   MeSH
• Mucoproteins MeSH
• Cell Line, Tumor MeSH
• Tumor Suppressor Protein p53 metabolism   MeSH
• Breast Neoplasms drug therapy   metabolism   pathology   MeSH
• Neoplasms drug therapy   metabolism   pathology   MeSH
• Oncogene Proteins MeSH
• Proteins metabolism   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Breast drug effects   metabolism   pathology   MeSH
• Aged MeSH
• Signal Transduction * drug effects   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• AGR2 protein, human MeSH Browser
• DUSP10 protein, human MeSH Browser
• Mitogen-Activated Protein Kinase Phosphatases MeSH
• Dual-Specificity Phosphatases MeSH
• p38 Mitogen-Activated Protein Kinases MeSH
• Mucoproteins MeSH
• Tumor Suppressor Protein p53 MeSH
• Oncogene Proteins MeSH
• Proteins MeSH
• Antineoplastic Agents MeSH