Role of coactivators in cell growth and tumorigenesis

描述（由申请人提供）：大量研究表明，癌基因和原癌基因通常通过解除对细胞周期的控制来诱导肿瘤发生。ACTR/AIB 1已被发现在许多类型的人类癌症中具有异常高的水平，包括乳腺癌。我们最近发现，ACTR/AIB 1可能在控制正常和癌细胞增殖中发挥重要作用，并且ACTR/AIB 1水平升高可能促进乳腺癌细胞不依赖于激素增殖并抵抗抗雌激素治疗。更重要的是，我们发现，当异位表达时，ACTR/AIB 1可以转化正常的人乳腺上皮细胞（HMEC），因此作为一个原癌基因。我们还发现，ACTR可能与原癌基因ErbB 2信号通路合作，刺激ER阴性乳腺癌细胞增殖。我们推测，ACTR的异常功能可能在乳腺癌的发生中起作用，通过上调关键细胞周期调节因子E2 Fs的转录活性，与ErbB 2信号传导合作，破坏细胞周期进程的正常控制机制。在这项研究中，我们将确定是否升高的ACTR控制ER阴性的人乳腺癌细胞的增殖与ErbB 2和ACTR作为E2 F辅激活剂在控制细胞周期基因表达的分子机制的合作。为了确定升高的ACTR在肿瘤发生中的作用，我们还将使用肿瘤异种移植模型和转基因模型来检查ACTR在肿瘤生长中的作用、ACTR的致癌潜力以及其与ErbB 2合作的能力。最后，我们将确定介导异常ACTR致癌功能的关键下游效应物。本研究的结果将为肿瘤中ACTR异常功能的药物筛选提供新的分子靶点和平台。它们也可能为我们理解正常和恶性细胞的细胞周期进展机制提供新的见解。

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.