Role of coactivators in cell growth and tumorigenesis

描述(由申请人提供)：大量研究表明，癌基因和原癌基因经常通过解除对细胞周期的控制来诱导肿瘤的发生。ACTR/AIB1已被发现在许多类型的人类癌症中异常高水平，包括乳腺癌。我们最近发现ACTR/AIB1可能在控制正常和癌细胞的增殖中发挥重要作用，ACTR/AIB1水平的升高可能促进乳腺癌细胞不依赖激素而增殖，并对抗雌激素治疗产生抵抗。更重要的是，我们发现，当ACTR/AIB1异位表达时，可以转化正常的人乳腺上皮细胞，从而发挥原癌基因的作用。我们还发现ACTR可能与原癌基因ErbB2信号协同刺激ER阴性的乳腺癌细胞增殖。我们推测，ACTR的异常功能可能通过上调关键细胞周期调节因子E2F的转录活性，与ErbB2信号协同作用，扰乱细胞周期进展的正常控制机制，从而在乳腺癌的发生中发挥作用。在这项研究中，我们将确定升高的ACTR是否与ErbB2协同控制ER阴性的人乳腺癌细胞的增殖，以及ACTR作为E2F共激活因子控制细胞周期基因表达的分子机制。为了确定ACTR升高在肿瘤发生中的作用，我们还将利用肿瘤移植模型和转基因模型来检测ACTR在肿瘤生长中的作用、ACTR的致癌潜力及其与ErbB2的协同作用。最后，我们将确定介导异常ACTR致癌功能的关键下游效应因子。本研究的结果将为筛选干扰ACTR在癌症中的异常功能的药物提供新的分子靶点和平台。它们还可能为我们理解正常和恶性细胞中细胞周期进展的机制提供新的见解。

DESCRIPTION (provided by applicant): Numerous studies indicate that oncogenes and proto-oncogenes often induce tumorigenesis by de-regulating the control of cell cycle. ACTR/AIB1 has been found to have abnormally high levels in many types of human cancers, including breast cancer. We have recently found that ACTR/AIB1 may play an important role in the control of normal and cancer cell proliferation, and that elevated levels of ACTR/AIB1 may promote breast cancer cells to proliferate independent of hormones and resist to anti-estrogen treatment. More significantly, we found that, when ectopically expressed, ACTR/AIB1 can transform normal human mammary epithelial cells (HMECs), therefore acting as a proto-oncogene. We also found that ACTR may cooperate with proto-oncogene ErbB2 signaling to stimulate ER-negative breast cancer cell proliferation. We hypothesize that aberrant function of ACTR may play a role in the initiation of breast cancer by disrupting the normal control mechanism of cell cycle progression through up-regulation of the transcriptional activity of the key cell cycle regulator E2Fs, in cooperation with ErbB2 signaling. In this study, we will determine whether elevated ACTR controls ER-negative human breast cancer cell proliferation in cooperation with ErbB2 and the molecular mechanism of ACTR action as an E2F coactivator in control of cell cycle gene expression. To determine the role of elevated ACTR in tumorigenesis, we will also use tumor xenograft model and transgenic model to examine the role of ACTR in tumor growth, ACTR's oncogenic potential and its ability to cooperate with ErbB2. Finally, we will determine the key downstream effectors that mediate the oncogenic function of aberrant ACTR. The results from this study will be valuable in providing novel molecular targets and platform for screening drugs that disrupt the aberrant function of ACTR in cancer. They will also likely provide new insight to our understanding the mechanism of cell cycle progression in normal and malignant cells.