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.