Role of coactivators in cell growth and tumorigenesis

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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.