RbAp46 Inhibits Estrogen-stimulated Progression of Neoplastigenic Breast Epithelial Cells

Abstract

Background: Despite widespread agreement that estrogens are involved in the etiology of human breast cancer, there is uncertainty as to the molecular mechanisms of estrogen action in early development of breast cancer. Materials and Methods: MCF10AT3B cells, a cell line derived from a xenograft model of human proliferative breast disease, were used to study the estrogen-stimulated malignant progression of neoplastigenic mammary epithelial cells. A stable cell line was established from MCF10AT3B cells that ectopically expresses the retinoblastoma suppressor (Rb)-associated protein 46 (RbAp46), a component of the histone modifying and remodeling complexes. Western blot and in vitro and in vivo growth assays were used to study the effects of constitutive RbAp46 expression on estrogen-stimulated cell proliferation. Results: Estrogen treatment down-regulated RbAp46 expression in MCF10AT3B cells. Constitutive RbAp46 expression inhibited estrogen-stimulated cell growth in vitro. In nude mice, RbAp46 expression strongly suppressed estrogen-stimulated tumorigenesis of MCF10AT3B cells. In RbAp46-expressing tumors, β-catenin protein was highly phosphorylated and the steady state levels of β-catenin protein were significantly reduced. Conclusion: RbAp46 plays an important role in the regulation of mitogenic estrogen signaling and dysregulated RbAp46 expression may contribute to estrogen-stimulated breast cancer development.