Proteomic Analysis Reveals Major Proteins and Pathways That Mediate the Effect of 17-β-Estradiol in Cell Division and Apoptosis in Breast Cancer MCF7 Cells

Despite extensive research, the genes/proteins and pathways
responsible
for the physiological effects of estrogen remain elusive. In this
study, we determined the effect of estrogen on global protein expression
in breast cancer MCF7 cells using a proteomic method. The expression
of 77 cytosolic, 74 nuclear, and 81 membrane/organelle proteins was
significantly altered by 17-β-estradiol (E2). Protein enrichment
analyses suggest that E2 may stimulate cell division primarily by
promoting the G1 to S phase transition and advancing the G2/M checkpoint.
The effect of E2 on cell survival was complex, as it could simultaneously
enhance and inhibit apoptosis. Bioinformatics analysis suggests that
E2 may enhance apoptosis by promoting the accumulation of the pore-forming
protein Bax in the mitochondria and inhibit apoptosis by activating
the PI3K/AKT/mTOR signaling pathway. We verified the activation of
the PI3K signaling and the accumulation of Bax in the membrane/organelle
fraction in E2-treated cells using immunoblotting. Treatment of MCF7
cells with E2 and the PI3K inhibitor Ly294002 significantly enhanced
apoptosis compared to those treated with E2 alone, suggesting that
combining estrogen with a PI3K inhibitor could be a promising strategy
for treating ERα-positive breast cancer. Interestingly, many
of the E2-upregulated proteins contained the HEAT, KH, and RRM domains.