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 α. 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)

Background: [¹⁸F]-Fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET/CT) may sometimes be suboptimal for imaging gastric adenocarcinoma. The recently introduced [⁶⁸Ga]Ga-FAPI-04 (FAPI) PET/CT targets tumor stroma and has shown considerable potential in evaluating the extent of disease in a variety of tumors. Methods: We performed a head-to-head prospective comparison of FAPI and FDG PET/CT in the same group of 13 patients with gastric adenocarcinoma who presented for either initial staging (n = 10) or restaging (n = 3) of disease. Lesion detection and maximum standardized uptake value (SUV_max) were compared between the two types of radiotracers. Results: All ten primary gastric tumors were FAPI-positive (100% detection rate), whereas only five were also FDG-positive (50%). SUV_max was not significantly different, but the tumor-to-background ratio was higher for FAPI (mean, median, and range of 4.5, 3.2, and 0.8–9.7 for FDG and 12.9, 11.9, and 2.2–23.9 for FAPI, P = 0.007). The level of detection of regional lymph node involvement was comparable. FAPI showed a superior detection rate for peritoneal carcinomatosis (100% vs. none). Two patients with widespread peritoneal carcinomatosis underwent a follow-up FAPI scan after chemotherapy: one showed partial remission and the other showed progressive disease. Conclusions: The findings of this pilot study suggest that FAPI PET/CT outperforms FDG PET/CT in detecting both primary gastric adenocarcinoma and peritoneal carcinomatosis from gastric cancer. FAPI PET/CT also shows promise for monitoring response to treatment in patients with peritoneal carcinomatosis from gastric cancer; however, larger trials are needed to validate these preliminary findings.