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[Cancer Research 66, 7818-7823, August 1, 2006]
© 2006 American Association for Cancer Research

Epidemiology and Prevention

15-Hydroxyprostaglandin Dehydrogenase Is a Tumor Suppressor of Human Breast Cancer

Ido Wolf1, James O'Kelly1, Tamar Rubinek2, Min Tong5, Anh Nguyen1, Bryan T. Lin4, Hsin-Hsiung Tai5, Beth Y. Karlan3 and H. Phillip Koeffler1

1 Division of Hematology/Oncology, 2 Division of Endocrinology, and the 3 Women's Cancer Research Institute, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, Los Angeles, California; 4 Department of Anatomic Pathology, Tarzana Regional Medical Center, Tarzana, California; and 5 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky

Requests for reprints: Ido Wolf, Division of Hematology/Oncology, Davis Building 5005, Cedars-Sinai Research Institute, University of California at Los Angeles School of Medicine, 8700 Beverly Boulevard, Los Angeles, CA 90048. Phone: 310-423-7759; Fax: 310-423-0225; E-mail: wolf-i{at}inter.net.il.

Prostaglandin E2 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. (Cancer Res 2006; 66(15): 7818-23)




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