Jeffy Brandon D, Hockings Jennifer K, Kemp Michael Q, Morgan Sherif S, Hager Jill A, Beliakoff Jason, Whitesell Luke J, Bowden G Timothy, Romagnolo Donato F
Cancer Biology Interdisciplinary Program, Arizona Health Sciences Center, Tuczon, AZ, USA.
Neoplasia. 2005 Sep;7(9):873-82. doi: 10.1593/neo.05256.
One of the puzzles in cancer predisposition is that women carrying BRCA-1 mutations preferentially develop tumors in epithelial tissues of the breast and ovary. Moreover, sporadic breast tumors contain lower levels of BRCA-1 in the absence of mutations in the BRCA-1 gene. The problem of tissue specificity requires analysis of factors that are unique to tissues of the breast. For example, the expression of estrogen receptor-alpha (ER alpha) is inversely correlated with breast cancer risk, and 90% of BRCA-1 tumors are negative for ER alpha. Here, we show that estrogen stimulates BRCA-1 promoter activity in transfected cells and the recruitment of ER alpha and its cofactor p300 to an AP-1 site that binds Jun/Fos transcription factors. The recruitment of ER alpha/p300 coincides with accumulation in the S-phase of the cell cycle and is antagonized by the antiestrogen tamoxifen. Conversely, we document that overexpression of wild-type p53 prevents the recruitment of ER alpha to the AP-1 site and represses BRCA-1 promoter activity. Taken together, our findings support a model in which an ER alpha/AP-1 complex modulates BRCA-1 transcription under conditions of estrogen stimulation. Conversely, the formation of this transcription complex is abrogated in cells overexpressing p53.
癌症易感性中的一个谜题是，携带BRCA-1突变的女性更易在乳腺和卵巢的上皮组织中发生肿瘤。此外，在BRCA-1基因无突变的情况下，散发性乳腺肿瘤中BRCA-1的水平较低。组织特异性问题需要分析乳腺组织特有的因素。例如，雌激素受体α（ERα）的表达与乳腺癌风险呈负相关，并且90%的BRCA-1肿瘤ERα呈阴性。在此，我们表明雌激素可刺激转染细胞中BRCA-1启动子活性，并促使ERα及其辅因子p300募集至与Jun/Fos转录因子结合的AP-1位点。ERα/p300的募集与细胞周期S期的积累同时发生，并被抗雌激素他莫昔芬所拮抗。相反，我们证明野生型p53的过表达可阻止ERα募集至AP-1位点，并抑制BRCA-1启动子活性。综上所述，我们的研究结果支持这样一种模型，即ERα/AP-1复合物在雌激素刺激条件下调节BRCA-1转录。相反，在过表达p53的细胞中，这种转录复合物的形成被消除。
