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

Abstract

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 ERα^1,2,3, 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.