Wang Chenguang, Fan Saijun, Li Zhiping, Fu Maofu, Rao Mahadev, Ma Yongxian, Lisanti Michael P, Albanese Chris, Katzenellenbogen Benita S, Kushner Peter J, Weber Barbara, Rosen Eliot M, Pestell Richard G
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia 20007, USA.
Cancer Res. 2005 Aug 1;65(15):6557-67. doi: 10.1158/0008-5472.CAN-05-0486.
The cyclin D1 gene is frequently overexpressed in human breast cancer and is capable of inducing mammary tumorigenesis when overexpressed in transgenic mice. The BRCA1 breast tumor susceptibility gene product inhibits breast cancer cellular growth and the activity of several transcription factors. Herein, cyclin D1 antagonized BRCA1-mediated repression of estrogen receptor alpha (ERalpha)-dependent gene expression. Cyclin D1 repression of BRCA1 function was mediated independently of its cyclin-dependent kinase, retinoblastoma protein, or p160 (SRC-1) functions in human breast and prostate cancer cells. In vitro, cyclin D1 competed with BRCA1 for ERalpha binding. Cyclin D1 and BRCA1 were both capable of binding ERalpha in a common region of the ERalpha hinge domain. A novel domain of cyclin D1, predicted to form a helix-loop-helix structure, was required for binding to ERalpha and for rescue of BRCA1-mediated ERalpha transcriptional repression. In chromatin immunoprecipitation assays, 17beta-estradiol (E2) enhanced ERalpha and cyclin D1 recruitment to an estrogen response element (ERE). Cyclin D1 expression enhanced ERalpha recruitment to an ERE. E2 reduced BRCA1 recruitment and BRCA1 expression inhibited E2-induced ERalpha recruitment at 12 hours. Cyclin D1 expression antagonized BRCA1 inhibition of ERalpha recruitment to an ERE, providing a mechanism by which cyclin D1 antagonizes BRCA1 function at an ERE. As cyclin D1 abundance is regulated by oncogenic and mitogenic signals, the antagonism of the BRCA1-mediated ERalpha repression by cyclin D1 may contribute to the selective induction of BRCA1-regulated target genes.
细胞周期蛋白D1基因在人类乳腺癌中经常过度表达，当在转基因小鼠中过度表达时能够诱发乳腺肿瘤发生。乳腺癌易感基因BRCA1的产物可抑制乳腺癌细胞生长以及几种转录因子的活性。在此，细胞周期蛋白D1拮抗BRCA1介导的雌激素受体α（ERα）依赖性基因表达的抑制作用。在人乳腺癌和前列腺癌细胞中，细胞周期蛋白D1对BRCA1功能的抑制作用独立于其细胞周期蛋白依赖性激酶、视网膜母细胞瘤蛋白或p160（SRC-1）的功能。在体外，细胞周期蛋白D1与BRCA1竞争结合ERα。细胞周期蛋白D1和BRCA1都能够在ERα铰链区的一个共同区域结合ERα。细胞周期蛋白D1的一个预测形成螺旋-环-螺旋结构的新结构域是结合ERα以及挽救BRCA1介导的ERα转录抑制所必需的。在染色质免疫沉淀试验中，17β-雌二醇（E2）增强了ERα和细胞周期蛋白D1募集到雌激素反应元件（ERE）上。细胞周期蛋白D1的表达增强了ERα募集到ERE上。E2在12小时时减少了BRCA1的募集，而BRCA1的表达抑制了E2诱导的ERα募集。细胞周期蛋白D1的表达拮抗了BRCA1对ERα募集到ERE的抑制作用，提供了一种细胞周期蛋白D1在ERE处拮抗BRCA1功能的机制。由于细胞周期蛋白D1的丰度受致癌和促有丝分裂信号调节，细胞周期蛋白D1对BRCA1介导的ERα抑制的拮抗作用可能有助于选择性诱导BRCA1调节的靶基因。
