Expression of Estrogen-Induced Genes and Estrogen Receptor β in Pancreatic Neuroendocrine Tumors

OBJECTIVE: The indolent nature and expression of progesterone receptor (PR), a well-known estrogen-induced gene, in a subset of pancreatic neuroendocrine tumors (PanNETs), raise the possibility of hormonal regulation in these tumors. METHODS: Immunohistochemical expression of estrogen receptors (ERs) α and β as well as messenger RNA expression of estrogen-induced genes (PR, EIG121, IGF-1, IGF-1R, sFRP1, and sFRP4) by quantitative reverse transcription-polymerase chain reaction were examined in 131 World Health Organization grade G1 and G2 PanNETs and correlated their expression with clinicopathological features. RESULTS: Thirty-nine PanNETs (30%) showed high positive ERβ staining, and 87 cases (66%) had low positive ERβ staining; only 5 cases (4%) had no nuclear staining. Pancreatic neuroendocrine tumors with small size (P = 0.02), low World Health Organization grade (P = 0.02), and low American Joint Committee on Cancer stage (P = 0.006) more frequently showed high positive ERβ staining. Among the estrogen-induced genes studied, PanNETs had significantly higher expression of PR, EIG121, IGF-1, sFRP1, and sFRP4 compared with normal pancreas, independent of age or sex. High positive ERβ staining was associated with an increased expression of PR (P < 0.001) and EIG121 (P = 0.02). CONCLUSIONS: Our study showed that PanNETs with favorable prognostic features have higher ERβ expression, which is associated with up-regulated PR and EIG121 messenger RNA expression. Estrogen regulation in PanNETs could potentially help in risk stratification and provide a rational target for novel treatment strategies.