Role of coactivators in cell growth and tumorigenesis

大量研究表明，癌基因和原癌基因常常通过去调节来诱导肿瘤的发生。 细胞周期的控制。已发现ACTR/AIB1在许多类型的人类中异常高水平 癌症，包括乳腺癌。我们最近发现ACTR/AIB1可能在 控制正常和癌细胞增殖，ACTR/AIB1水平升高可能促进乳房 癌细胞的增殖不依赖于激素，并能抵抗抗雌激素治疗。更重要的是， 我们发现，当ACTR/AIB1异位表达时，可以转化正常的人类乳腺上皮 细胞(HMECs)，因此起原癌基因的作用。我们还发现，ACTR可能与Proto-2协同作用。 癌基因ErbB2信号转导刺激ER阴性乳腺癌细胞增殖。我们假设 ACTR功能异常可能通过破坏正常对照而在乳腺癌的发生中发挥作用 上调关键细胞周期转录活性的细胞周期进展机制 调节器E2FS，与ErbB2信令合作。在这项研究中，我们将确定提升的 ACTR与ErbB2和ACTR共同控制ER阴性的人乳腺癌细胞增殖 ACTR作为E2F共激活因子调控细胞周期基因表达的分子机制。至 确定ACTR升高在肿瘤发生中的作用，我们还将使用肿瘤异种移植模型和 转基因模型检测ACTR在肿瘤生长中的作用及ACTR的致癌潜能和能力 与ErbB2合作。最后，我们将确定介导致癌作用的关键下游效应因子。 异常ACTR的功能。这项研究的结果将对提供新的分子靶标有价值。 以及筛选破坏ACTR在癌症中异常功能的药物的平台。他们还很可能 为我们理解正常和恶性细胞周期进程的机制提供了新的视角 细胞。

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.