RbAp46 inhibits estrogen-stimulated progression of neoplastigenic breast epithelial cells.
RbAp46 inhibits estrogen-stimulated progression of neoplastigenic breast epithelial cells.
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发表时间：
2007-09
影响因子：
2
通讯作者：
Teng-fei Zhang;Shui-Qing Yu;Zhaoyi Wang
中科院分区：
文献类型：
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作者：
Teng-fei Zhang;Shui-Qing Yu;Zhaoyi Wang
背景：尽管人们普遍认为雌激素与人类乳腺癌的病因有关，但雌激素在乳腺癌早期发展过程中的分子作用机制尚不明确。材料与方法以人乳腺增生性疾病异种移植模型MCF10AT3B细胞为研究对象，研究雌激素对乳腺上皮细胞恶性转化的影响。从MCF10AT3B细胞中建立了一个稳定的细胞系，该细胞异位表达视网膜母细胞瘤抑制因子(Rb)相关蛋白46(RbAp46)，RbAp46是组蛋白修饰和重塑复合体的组成部分。采用Western印迹、体外和体内生长实验研究RbAp46结构性表达对雌激素刺激的细胞增殖的影响。结果雌激素可下调MCF10AT3B细胞RbAp46的表达。RbAp46的结构性表达在体外抑制雌激素刺激的细胞生长。在裸鼠体内，RbAp46的表达强烈抑制雌激素刺激的MCF10AT3B细胞的成瘤。在表达RbAp46的肿瘤中，β-连环蛋白高度磷酸化，稳态水平显著降低。结论RbAp46在促有丝分裂激素信号转导中起重要作用，RbAp46表达异常可能参与雌激素刺激乳腺癌的发生发展。
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 downregulated 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, beta-catenin protein was highly phosphorylated and the steady state levels of beta-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.