Martin Kristian Thomsen

Loss of JUNB/AP-1 promotes invasive prostate cancer

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • M K Thomsen
  • L Bakiri, Genes, Development and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), Madrid, Spain.
  • ,
  • Sebastian C Hasenfuss, Genes, Development and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), Madrid, Spain.
  • ,
  • H. Wu, Genes, Development and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), Madrid, Spain.
  • ,
  • M Morente, Biobank, National Cancer Research Centre (CNIO), Madrid, Spain.
  • ,
  • E F Wagner, Genes, Development and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), Madrid, Spain.

Prostate cancer is a frequent cause of male death in the Western world. Relatively few genetic alterations have been identified, likely owing to disease heterogeneity. Here, we show that the transcription factor JUNB/AP-1 limits prostate cancer progression. JUNB expression is increased in low-grade prostate cancer compared with normal human prostate, but downregulated in high-grade samples and further decreased in all metastatic samples. To model the hypothesis that this downregulation is functionally significant, we genetically inactivated Junb in the prostate epithelium of mice. When combined with Pten (phosphatase and tensin homologue) loss, double-mutant mice were prone to invasive cancer development. Importantly, invasive tumours also developed when Junb and Pten were inactivated in a small cell population of the adult anterior prostate by topical Cre recombinase delivery. The resulting tumours displayed strong histological similarity with human prostate cancer. Loss of JunB expression led to increased proliferation and decreased senescence, likely owing to decreased p16(Ink4a) and p21(CIP1) in epithelial cells. Furthermore, the tumour stroma was altered with increased osteopontin and S100 calcium-binding protein A8/9 expression, which correlated with poor prognoses in patients. These data demonstrate that JUNB/AP-1 cooperates with PTEN signalling as barriers to invasive prostate cancer, whose concomitant genetic or epigenetic suppression induce malignant progression.

Original languageEnglish
JournalCell Death and Differentiation
Volume22
Issue4
Pages (from-to)574-82
Number of pages9
ISSN1350-9047
DOIs
Publication statusPublished - Apr 2015
Externally publishedYes

    Research areas

  • Aging, Animals, Calgranulin A, Calgranulin B, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21, Disease Progression, Down-Regulation, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplasm Invasiveness, Osteopontin, PTEN Phosphohydrolase, Prostatic Neoplasms, RNA, Messenger, Signal Transduction, Transcription Factors, Journal Article, Research Support, Non-U.S. Gov't

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