The proliferation effects of fluoxetine and amitriptyline on human breast cancer cells and the underlying molecular mechanisms.

Abstract Some studies have suggested possible estrogen actions for antidepressants such as fluoxetine. However, the specific molecular mechanisms remain unclear. In this study, the molecular mechanism of fluoxetine-induced the proliferation of breast cancer SKBR3 and MCF-7 cells was evaluated by detecting ERα and GPR30-mediated ERK and PI3K/AKT signals. We found that low concentrations of fluoxetine upregulated the expression of GPR30, ERα, CyclinD1, and C-MYC proteins, as well as elevated the phosphorylation of ERK and AKT. The phosphorylation of ERK and AKT decreased when the cells were pretreated with ERα inhibitor ICI, GPR30 inhibitor G15, and PI3K inhibitor WM prior to fluoxetine exposure. The addition of these inhibitors also attenuated the fluoxetine-induced cell proliferation. These findings indicated that fluoxetine activated the PI3K/AKT and ERK signaling cascades via GPR30 to derive the cell proliferation. It suggests that fluoxetine has the potential to exert estrogen actions via GPR30.