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Molecular and Cellular Biology, June 2004, p. 5157-5171, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5157-5171.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

ACTR/AIB1 Functions as an E2F1 Coactivator To Promote Breast Cancer Cell Proliferation and Antiestrogen Resistance

Maggie C. Louie, June X. Zou, Alina Rabinovich, and Hong-Wu Chen*

Department of Biological Chemistry, School of Medicine, UCD Cancer Center/Basic Science, University of California at Davis, Sacramento, California 95817

Received 6 January 2004/ Returned for modification 3 February 2004/ Accepted 24 March 2004

Overexpression or amplification of ACTR (also named AIB1, RAC3, p/CIP, TRAM-1, and SRC-3), a member of the p160 family of coactivators for nuclear hormone receptors, has been frequently detected in multiple types of human tumors, including breast cancer. However, its role in cancer cell proliferation and the underlying mechanism are unclear. Here, we show that overexpression of ACTR not only enhances estrogen-stimulated cell proliferation but also, more strikingly, completely negates the cell cycle arrest effect by tamoxifen and pure antiestrogens. Unexpectedly, we found that ACTR directly interacts, through its N-terminal domain, with E2F1 and is recruited to E2F target gene promoters. Elevation of ACTR in quiescent cells strongly stimulates the transcription of a subset of E2F-responsive genes that are associated with the G1/S transition. We also demonstrated, by adenovirus vector-mediated RNA interference, that ACTR is required for E2F1-mediated gene expression and the proliferation of estrogen receptor (ER)-negative breast cancer cells. Moreover, the ability of elevated ACTR to promote estrogen-independent cell proliferation depends on the function of E2F1 and the association between ACTR and E2F1, but not ER. Thus, our results reveal an essential role of ACTR in control of breast cancer cell proliferation and implicate the ACTR-E2F1 pathway as a novel mechanism in antiestrogen resistance.

* Corresponding author. Mailing address: Department of Biological Chemistry, School of Medicine, UCD Cancer Center/Basic Science, University of California at Davis, UCDMC Res III, Rm. 1400B, 4645 2nd Ave., Sacramento, CA 95817. Phone: (916) 734-7743. Fax: (916) 734-0190. E-mail: hwzchen{at}ucdavis.edu.

Molecular and Cellular Biology, June 2004, p. 5157-5171, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5157-5171.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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