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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA113860-01A1
Application #
7033546
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Snyderwine, Elizabeth G
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
1
Fiscal Year
2006
Total Cost
$233,485
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Hsia, Elaine Y C; Zou, June X; Chen, Hong-Wu (2009) The roles and action mechanisms of p160/SRC coactivators and the ANCCA coregulator in cancer. Prog Mol Biol Transl Sci 87:261-98
Zou, June X; Revenko, Alexey S; Li, Li B et al. (2007) ANCCA, an estrogen-regulated AAA+ ATPase coactivator for ERalpha, is required for coregulator occupancy and chromatin modification. Proc Natl Acad Sci U S A 104:18067-72