Efp targets 14-3-3σ for proteolysis and promotes breast tumour growth

Oestrogen exerts its influence on target organs through activating oestrogen receptors (ERs) and regulating downstream genes by means of their oestrogen-responsive elements. Efp, a target gene product of ERα1,2,3, is a member of the RING-finger B-box coiled-coil (RBCC) motif family4. Efp is predominantly expressed in various female organs2 as well as in breast cancers5, and is thought to be essential for oestrogen-dependent cell proliferation and organ development—Efp-disrupted mice display underdeveloped uteri and reduced oestrogen responsiveness6. Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3σ, a negative cell cycle regulator that causes G2 arrest7. We demonstrate that tumour growth of breast cancer MCF7 cells implanted in female athymic mice is reduced by treatment with antisense Efp oligonucleotide. Efp-overexpressing MCF7 cells in ovariectomized athymic mice generate tumours in the absence of oestrogen. Loss of Efp function in mouse embryonic fibroblasts results in an accumulation of 14-3-3σ, which is responsible for reduced cell growth. These data provide an insight into the cell-cycle machinery and tumorigenesis of breast cancer by identifying 14-3-3σ as a target for proteolysis by Efp, leading to cell proliferation.