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15-hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer.

Abstract
Prostaglandin E(2) plays a growth-stimulatory role in breast cancer, and the rate-limiting enzyme in its synthesis, cyclooxygenase-2, is often overexpressed in these cancers. Little is known about the role of the key prostaglandin catabolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in breast cancer pathogenesis. Using a pharmacologically based screen for epigenetically silenced genes, we found low levels of 15-PGDH in MDA-MB-231 cells [estrogen receptor (ER) negative] but high levels in MCF-7 cells (ER positive) and observed its up-regulation following demethylation treatment. Further analysis revealed methylation of the 15-PGDH promoter in one breast cancer cell line and 30% of primary tumors. Analysis of 15-PGDH expression revealed low levels in 40% of primary breast tumors and identified a correlation between 15-PGDH and ER expression. Transfection assays showed that transient up-regulation of 15-PGDH levels in MDA-MB-231 cells resulted in a decreased clonal growth, and stable up-regulation significantly decreased the ability of these cells to form tumors in athymic mice. In contrast, transient silencing of 15-PGDH in MCF-7 cells resulted in their enhanced proliferation, and a stable silencing in these cells enhanced cell cycle entry in vitro and tumorigenicity in vivo. Forced expression of 15-PGDH inhibited the ER pathway and silencing of 15-PGDH up-regulated expression of aromatase. In addition, 15-PGDH levels were down-regulated by estrogen but up-regulated by the tumor suppressor gene CAAT/enhancer binding protein alpha. Our results indicate for the first time that 15-PGDH may be a novel tumor suppressor gene in breast cancer, and suggest that this enzyme can modulate the ER pathway.
AuthorsIdo Wolf, James O'Kelly, Tamar Rubinek, Min Tong, Anh Nguyen, Bryan T Lin, Hsin-Hsiung Tai, Beth Y Karlan, H Phillip Koeffler
JournalCancer research (Cancer Res) Vol. 66 Issue 15 Pg. 7818-23 (Aug 01 2006) ISSN: 0008-5472 [Print] United States
PMID16885386 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • RNA, Small Interfering
  • Receptors, Estrogen
  • Hydroxyprostaglandin Dehydrogenases
  • 15-hydroxyprostaglandin dehydrogenase
Topics
  • Animals
  • Base Sequence
  • Breast Neoplasms (enzymology, genetics)
  • Cell Growth Processes
  • Cell Line, Tumor
  • DNA Methylation
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Humans
  • Hydroxyprostaglandin Dehydrogenases (biosynthesis, genetics)
  • Mice
  • Mice, Nude
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • RNA, Small Interfering (genetics)
  • Receptors, Estrogen (biosynthesis)
  • Transfection
  • Up-Regulation

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