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Downregulation of 15-hydroxyprostaglandin dehydrogenase in hormone-resistant breast cancer

  • M Cummings
  • L Maraqa
  • MB Peter
  • AM Shaaban
  • AM Hanby
  • MA Hull
  • V Speirs
Poster presentation
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Keywords

Breast Cancer Tamoxifen Estrogen Receptor Alpha Endocrine Resistance Primary Human Breast 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Background

Tamoxifen has been the principal endocrine therapy for estrogen receptor alpha (ERα)-positive breast cancer patients and still remains the therapy of choice in the premenopausal setting. However, resistance and recurrence remain a serious problem. Our previous work has indicated that 15-hydroxyprostaglandin dehydrogenase (15-PGDH) was significantly down-regulated in two, independently derived, tamoxifen-resistant (TAMr) MCF-7 derivatives compared with sensitive controls [1]. 15-PGDH is the key enzyme for the biological inactivation of prostaglandins, and has been shown to be a tumour suppressor in breast cancer. However, a role for 15-PGDH downregulation in endocrine resistance has not previously been identified.

Methods and results

Downregulation of 15-PGDH mRNA and protein in TAMr MCF-7 was confirmed by quantitative RT-PCR and western blotting. To determine the role of 15-PGDH in TAMr, we stably transfected TAMr MCF-7 cells with human 15-PGDH cDNA. Overexpression of 15-PGDH partially restored sensitivity of TAMr cells to 4-hydroxytamoxifen by the MTT assay, demonstrating that 15-PGDH downregulation plays a functional role in the acquisition of TAMr. Treatment of TAMr MCF-7 cells with a DNA methyl-transferase inhibitor (5-azacytidine), and a histone deacetylase inhibitor (trichostatin A), led to re-expression of 15-PGDH mRNA (by quantitative RT-PCR), suggesting that 15-PGDH is silenced via epigenetic mechanisms during the acquisition of TAMr. To address whether 15-PGDH downregulation is involved in clinical TAMr, we assembled a tissue microarray comprising 89 relapsed primary human breast cancers and 234 tamoxifen-sensitive controls. We are currently optimizing 15-PGDH immunohistochemistry on our tissue microarrays, and results will be presented.

Conclusion

Our data suggest that the acquisition of TAMr in vitro involves epigenetic silencing of 15-PGDH. Moreover, our data show that 15-PGDH downregulation has a novel, functional role in endocrine resistance.

References

  1. 1.
    Scott DJ, Parkes AT, Ponchel F, Cummings M, Poola I, Speirs V: Changes in expression of steroid receptors, their downstream target genes and their associated co-regulators during the sequential acquisition of tamoxifen resistance in vitro. Int J Oncol. 2007, 31: 557-565.PubMedGoogle Scholar

Copyright information

© BioMed Central Ltd 2008

Authors and Affiliations

  • M Cummings
    • 1
  • L Maraqa
    • 1
  • MB Peter
    • 1
  • AM Shaaban
    • 1
  • AM Hanby
    • 1
  • MA Hull
    • 1
  • V Speirs
    • 1
  1. 1.Leeds Institute of Molecular Medicine, St James's University HospitalLeedsUK

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