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Volume 10 Supplement 2

Breast Cancer Research 2008

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

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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.

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Cummings, M., Maraqa, L., Peter, M. et al. Downregulation of 15-hydroxyprostaglandin dehydrogenase in hormone-resistant breast cancer. Breast Cancer Res 10, P30 (2008) doi:10.1186/bcr1914

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Keywords

  • Breast Cancer
  • Tamoxifen
  • Estrogen Receptor Alpha
  • Endocrine Resistance
  • Primary Human Breast