Naringenin induces different proliferative effects in estrogen receptor-alpha-66 negative breast cancer cells

Abstract Naringenin is a flavanone able to suppress the growth of various cancer cells including estrogen receptor-alpha-66 (ERα66)-positive breast cancer cells, but the anti-tumorigenic roles of naringenin in ERα66-negative breast cancer remain unclear. This study aims to determine the potential effects of naringenin on two ERα66-negative breast cancer cells (SKBR3 and MDA-MB-231) and to define their mechanisms of action. Herein, several cellular biological behaviors, including cell viability, migration, cycle, apoptosis, reactive oxygen species (ROS) generation, and oxidative stress (e.g., LDH, SOD and GSH), were evaluated in the present study. Then the gene expression levels involved in cell migration, cycle and apoptosis, as well as two membrane estrogen receptors (ERα36 and GPR30) were analyzed with real-time quantitative polymerase chain reaction (RT-qPCR) assay and western blotting. Results showed that naringenin exerted a concentration-dependent response on the growth of both ERα66-negative cell lines. The cell growth regulation was accompanied by modulation of cell migration, cycle and apoptosis, which were dependent on the ROS-regulated p53 signaling cascade. Importantly, ERα36 and GPR30 were involved in the (anti)-proliferative effects. These findings indicate naringenin possesses contrasting effects on ERα66-negative breast cancer cell growth depending on its dose