207 Background: The role of estrogen receptor (ER) signaling in pancreatic cancer is unknown. Recently, we demonstated that expression of the isoform ER beta correlates with an adverse prognosis in patients with pancreatic cancer. Here, we show that raloxifene, a specific estrogen receptor modulator (SERM), suppresses in vitro and in vivo tumor growth by interfering with ER beta signaling in human pancreatic adenocarcinoma. Methods: The human pancreatic adenocarcinoma cell line L3.6pl was cultured and exposed to raloxifene in vitro, and cell proliferation was determined by the BrdU assay. To analyze the specificity of raloxifene induced effects, ER knockdown was performed using siRNA specific for ER alpha and ER beta. In an in vivo model of orthotopic tumor xenografts in nude mice, raloxifene was administered daily, and tumor growth was monitored. Expression of ER beta and the proliferation marker Ki-67 were determined by immunohistochemistry. Results: Raloxifene treatment resulted in a potent, dose dependent reduction of proliferation in vitro over a nanomolar dose range. This effect was completely reversed by siRNA knockdown of ER beta, but not ER alpha, indicating an ER isotype specific signaling. In vivo, orthotopic tumor growth, as well as lymph node and liver metastases, was significantly suppressed in raloxifene treated mice. Analogous to the in vitro data, Ki-67 expression in vivo was significantly reduced in raloxifene treated mice, while ER beta expression was not changed in vivo. Conclusions: Inhibition of ER beta signaling by raloxifene results in a potent reduction of human pancreatic adenocarcinoma growth in vitro and in vivo. Treatment with SERMs may be an attractive therapeutic option in subjects expressing the ER beta isotype. No significant financial relationships to disclose.
Mutation of the palmitoylation site of estrogen receptor in vivo reveals tissue-specific roles for membrane versus nuclear actions