Regulation of estrogenic effects by Beclin 1 in breast cancer cells

Beclin 1 is an essential mediator of autophagy and a regulator of cell growth and cell death. We examined the effect of Beclin 1 overexpression on the action of estradiol (E-2) and two antiestrogens, raloxifene and 4-hydroxytamoxifen, in estrogen receptor alpha (ER alpha)-positive MCF-7 breast cancer cells. [H-3]thymidine incorporation studies showed that Berlin 1-overexpressing cells (MCF-7.beclin) had a lower proliferative response to E-2 compared with cells transfected with vector control (MCF-7.control). There was only a 35% increase in [H-3]-thymidine incorporation, after 24 hours of E-2 treatment of MCF-7.beclin cells compared with untreated cells, whereas this increase was 2-fold for MCF-7.control cells. E-2-induced changes in the expression of early-response genes were examined by real-time quantitiative PCR. There were significant differences in the pattern of expression of E-2-induced genes c-myc, c-fos, Erg-1, and Nur77 between MCF-7.beclin and MCF-7.control cells two hours after treatment. Although E2-induced growth of MCF-7.control cells was completely inhibited by 500 nmol/L raloxifene or 500 nmol/L 4-hydroxytamoxifen, these concentrations of antiestrogens had no significant effect on the growth of MCF-7.beclin cells. Confocal microscopic and coimmunoprecipitation studies showed evidence for colocalization and association of Beclin I and ER alpha In addition, E-2 caused a decrease in Akt phosphorylation in MCF-7.beclin cells, compared with a 3-fold increase in MCF-7 cells, five minutes after treatment. These results indicate that Beclin I can down-regulate estrogenic signaling and growth response, and contribute to the development of antiestrogen resistance. This observation might be useful to define and overcome antiestrogen resistance of breast cancer.