title: AGR2 oncoprotein inhibits p38 MAPK and p53 activation through a DUSP10-mediated regulatory pathway.
abstract: 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.
authors.affiliation: Regional Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic.
authors.forename: Roman
authors.initials: R
authors.lastname: Hrstka
authors.affiliation: Regional Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Bouchalova
authors.affiliation: Regional Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Michalova
authors.affiliation: Regional Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Matoulkova
authors.affiliation: Regional Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Muller
authors.affiliation: Regional Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Coates
authors.affiliation: Regional Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic. Electronic address: vojtesek@mou.cz.
authors.forename: Borivoj
authors.initials: B
authors.lastname: Vojtesek
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D054637:Dual-Specificity Phosphatases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008875:Middle Aged; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism*; D009088:Mucoproteins; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015513:Oncogene Proteins; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C502296:AGR2 protein, human; D000970:Antineoplastic Agents; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; C120407:DUSP10 protein, human; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases
keywords: AGR2; Breast cancer; DUSP10; Drug resistance; p38 MAPK; p53