乳腺癌中Ets-1与Ets-2以及共调节蛋白SRC-1、AIB1和NCoR之间的关联与相互作用。

Associations and interactions between Ets-1 and Ets-2 and coregulatory proteins, SRC-1, AIB1, and NCoR in breast cancer.

作者信息

Myers Eddie, Hill Arnold D K, Kelly Gabrielle, McDermott Enda W, O'Higgins Niall J, Buggy Yvonne, Young Leonie S

机构信息

Department of Surgery, Saint Vincent's University Hospital University College Dublin, Dublin 4, Ireland.

出版信息

Clin Cancer Res. 2005 Mar 15;11(6):2111-22. doi: 10.1158/1078-0432.CCR-04-1192.

DOI:10.1158/1078-0432.CCR-04-1192

PMID:15788656

Abstract

PURPOSE

Associations between p160 coactivator proteins and the development of resistance to endocrine treatment have been described. We hypothesized that nuclear receptor coregulatory proteins may interact with nonsteroid receptors. We investigated the mitogen-activated protein kinase-activated transcription factors, Ets, as possible interaction proteins for the coactivators SRC-1 and AIB1 and the corepressor NCoR in human breast cancer.

EXPERIMENTAL DESIGN

Expression and coexpression of Ets and the coregulatory proteins was investigated using immunohistochemistry and immunofluorescence in a cohort of breast tumor patients (N = 134). Protein expression, protein-DNA interactions and protein-protein interactions were assessed using Western blot, electromobility shift, and coimmunoprecipitation analysis, respectively.

RESULTS

Ets-1 and Ets-2 associated with reduced disease-free survival (P < 0.0292, P < 0.0001, respectively), whereas NCoR was a positive prognostic indicator (P < 0.0297). Up-regulation of Ets-1 protein expression in cell cultures derived from patient tumors in the presence of growth factors associated with tumor grade (P < 0.0013; n = 28). In primary breast tumor cell cultures and in the SKBR3 breast cell line, growth factors induced interaction between Ets and their DNA response element, induced recruitment of coactivators to the transcription factor-DNA complex, and up-regulated protein expression of HER2. Ets-1 and Ets-2 interacted with the coregulators under basal conditions, and growth factors up-regulated Ets-2 interaction with SRC-1 and AIB1. Coexpression of Ets-2 and SRC-1 significantly associated with the rate of recurrence and HER expression, compared with patients who expressed Ets-2 but not SRC-1 (P < 0.0001 and P < 0.0001, respectively).

CONCLUSIONS

These data describe associations and interactions between nonsteroid transcription factors and coregulatory proteins in human breast cancer.

摘要

目的

p160共激活蛋白与内分泌治疗耐药性的发展之间的关联已被描述。我们推测核受体共调节蛋白可能与非甾体受体相互作用。我们研究了丝裂原活化蛋白激酶激活的转录因子Ets，作为人乳腺癌中共激活因子SRC-1和AIB1以及共抑制因子NCoR的可能相互作用蛋白。

实验设计

使用免疫组织化学和免疫荧光在一组乳腺肿瘤患者（N = 134）中研究Ets和共调节蛋白的表达及共表达情况。分别使用蛋白质印迹、电泳迁移率变动分析和免疫共沉淀分析评估蛋白质表达、蛋白质-DNA相互作用和蛋白质-蛋白质相互作用。

结果

Ets-1和Ets-2与无病生存期缩短相关（分别为P < 0.0292，P < 0.0001），而NCoR是一个阳性预后指标（P < 0.0297）。在存在与肿瘤分级相关的生长因子的情况下，患者肿瘤来源的细胞培养物中Ets-1蛋白表达上调（P < 0.0013；n = 28）。在原发性乳腺肿瘤细胞培养物和SKBR3乳腺癌细胞系中，生长因子诱导Ets与其DNA反应元件之间的相互作用，诱导共激活因子募集到转录因子-DNA复合物中，并上调HER2的蛋白表达。在基础条件下，Ets-1和Ets-2与共调节因子相互作用，生长因子上调Ets-2与SRC-1和AIB1的相互作用。与表达Ets-2但不表达SRC-1的患者相比，Ets-2和SRC-1的共表达与复发率和HER表达显著相关（分别为P < 0.0001和P < 0.0001）。