Important roles of estrogen receptor alpha in tumor progression and anti-estrogen therapy of pancreatic ductal adenocarcinoma

Aims: The roles of estrogen receptors (ERs) and the efficacy of anti-estrogen (E2) therapies in pancreatic cancer stay controversial. The main objectives of this study were to investigate the potential roles of ERs in tumor progression and endocrine therapies. Main methods: The ER expression status in PANG-1 and SW1990 pancreatic cancer cell lines was determined. SRB assay, colony formation assay and proliferation assay were used to investigate the responses of these cells to E2. ER alpha-selective agonist propylpyrazoletriol (PPT), ER beta-selective agonist diarylpropionitrile (DPN), ER alpha overexpressed SW1990 cells, ER alpha knock-out PANG-1 cells and patient-derived xenografts (PDX) were applied to investigate the potential roles of ER alpha in pancreatic cancer. The phosphorylation of ER alpha-related signaling molecules extracellular regulated protein kinases (ERK1/2) and protein kinase B (AKT) were investigated. The in vivo anti-tumor efficacy and safety of letrozole (LTZ) combined with leuprorelin acetate (LA) and gemcitabine (GEM) were also preliminarily studied. Key findings: PANG-1 cells expressed much more ERa than SW1990 cells, and ER beta level was with less diversity. Accordingly, the proliferation of PANG-1 rather than SW1990 cells could be stimulated by E2, and only PANG-1 could respond to LTZ endocrine therapy in female but not male mice. The phosphorylation of ERK1/2 but not AKT was altered by over-expressed or knocking out of ER alpha with or without the addition of E2 and LTZ. The combination therapy of LTZ and GEM showed acceptable efficacy and safety. Significance: This study showed the important roles of ER alpha in tumor progression and endocrine therapies of pancreatic cancer in women.