Most of the breast
cancers initially respond to endocrine
therapy that reduces the levels of
estrogens or competes with
estrogen for binding to its receptor. Most of the patients, however, acquire resistance to endocrine
therapy with
tamoxifen and
aromatase inhibitors later. We assumed that identification of
estrogen-responsive genes those regulate the growth of
breast cancer is indispensable to develop new strategies targeting the genes and overcome the resistance to current endocrine
therapy.
Estrogen-responsive finger
protein (Efp) is one of the
estrogen receptor (ER)-target genes we have cloned using genomic binding site cloning. Efp features a structure of the RING-finger B-box coiled-coil (RBCC) motif. We postulated that Efp is a critical factor in proliferation of
breast tumors. In a model system using MCF7 cells grown in xenografts, we showed that inhibition of Efp expression by
antisense oligonucleotide reduced the
tumor growth. MCF7 cells overexpressing Efp formed
tumors in xenografts even in
estrogen deprivation environment. By yeast two-hybrid screen, we identified that Efp interacts with 14-3-3sigma, which is known as a cell cycle brake that causes G2 arrest and expressed in normal mammary glands. In vitro studies have revealed that Efp functions as a
ubiquitin-protein ligase (E3) that targets 14-3-3sigma. These data suggest that Efp controls
breast cancer growth through
ubiquitin-dependent proteolysis of 14-3-3sigma. Future studies may provide a new
therapy to block
breast tumor proliferation by targeting Efp.