Skip to main content

Volume 10 Supplement 2

Breast Cancer Research 2008

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


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.


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.


  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.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cummings, M., Maraqa, L., Peter, M. et al. Downregulation of 15-hydroxyprostaglandin dehydrogenase in hormone-resistant breast cancer. Breast Cancer Res 10 (Suppl 2), P30 (2008).

Download citation

  • Published:

  • DOI:


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