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AGR2 oncoprotein inhibits p38 MAPK and p53 activation through a DUSP10-mediated regulatory pathway

Roman Hrstka1, Pavla Bouchalova1, Eva Michalova1

  • 1Regional Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic.

Molecular Oncology
|January 7, 2016
PubMed

Insights

A newly discovered pathway involving AGR2 and DUSP10 suppresses tumor suppressor p53 activity in certain cancers. This finding offers new therapeutic strategies for wild-type p53 cancers, particularly in ER+ breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • The tumor suppressor p53 is crucial in preventing cancer, but its activity is often diminished in tumors through various mechanisms.
  • While p53 mutations are common, other pathways attenuate p53 function in wild-type p53 cancers, including alterations in upstream regulators and signaling pathways.
  • Identifying novel mechanisms that reduce p53 tumor suppressor activity is essential for understanding cancer development and devising new therapies.

Purpose of the Study:

  • To identify and characterize a novel signaling pathway responsible for attenuating p53 activity in human cancers.
  • To investigate the role of AGR2 and its downstream targets in modulating p53 function and its impact on cancer prognosis.
  • To explore the therapeutic implications of targeting this newly identified pathway in wild-type p53 cancers.

Main Methods:

  • Utilized human cancer data to identify novel pathways affecting p53 activity.
  • Demonstrated that AGR2 overexpression up-regulates DUSP10, which inhibits p38 MAPK.
  • Analyzed human breast cancer datasets to assess the prognostic significance of AGR2 and DUSP10 in specific patient subgroups.

Main Results:

  • Identified a novel pathway where AGR2 up-regulates DUSP10, inhibiting p38 MAPK and preventing p53 phosphorylation and activation.
  • AGR2 overexpression is linked to a poor prognosis in estrogen receptor-positive (ER+) breast cancers with wild-type p53.
  • DUSP10 levels also demonstrated prognostic significance in this specific ER+ wild-type p53 breast cancer subgroup.

Conclusions:

  • Discovered a new pro-oncogenic signaling pathway involving AGR2 and DUSP10 that confers resistance to DNA-damaging agents by inhibiting p53.
  • This pathway's specific impact on ER+ wild-type p53 breast cancers highlights a critical therapeutic vulnerability.
  • Findings suggest novel strategies for modulating wild-type p53 activity in cancer treatment by targeting the AGR2-DUSP10-p38 MAPK axis.
Keywords:
AGR2Breast cancerDUSP10Drug resistancep38 MAPKp53

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