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Molecular and Cellular Biology, October 2008, p. 5937-5950, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00579-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The AIB1 Oncogene Promotes Breast Cancer Metastasis by Activation of PEA3-Mediated Matrix Metalloproteinase 2 (MMP2) and MMP9 Expression{triangledown}

Li Qin,1,{dagger} Lan Liao,1,{dagger} Aisling Redmond,2 Leonie Young,2 Yuhui Yuan,1 Hongwu Chen,3 Bert W. O'Malley,1 and Jianming Xu1*

Department of Molecular and Cellular Biology and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030,1 Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland,2 UC Davis Cancer Center/Basic Science, University of California at Davis, Sacramento, California 958173

Received 9 April 2008/ Returned for modification 22 May 2008/ Accepted 10 July 2008

Amplified-in-breast cancer 1 (AIB1) is an overexpressed transcriptional coactivator in breast cancer. Although overproduced AIB1 is oncogenic, its role and underlying mechanisms in metastasis remain unclear. Here, mammary tumorigenesis and lung metastasis were investigated in wild-type (WT) and AIB1–/– mice harboring the mouse mammary tumor virus-polyomavirus middle T (PyMT) transgene. All WT/PyMT mice developed massive lung metastasis, but AIB1–/–/PyMT mice with comparable mammary tumors had significantly less lung metastasis. The recipient mice with transplanted AIB1–/–/PyMT tumors also had much less lung metastasis than the recipient mice with transplanted WT/PyMT tumors. WT/PyMT tumor cells expressed mesenchymal markers such as vimentin and N-cadherin, migrated and invaded rapidly, and formed disorganized cellular masses in three-dimensional cultures. In contrast, AIB1–/–/PyMT tumor cells maintained epithelial markers such as E-cadherin and ZO-1, migrated and invaded slowly, and still formed polarized acinar structures in three-dimensional cultures. Molecular analyses revealed that AIB1 served as a PEA3 coactivator and formed complexes with PEA3 on matrix metalloproteinase 2 (MMP2) and MMP9 promoters to enhance their expression in both mouse and human breast cancer cells. In 560 human breast tumors, AIB1 expression was found to be positively associated with PEA3, MMP2, and MMP9. These findings suggest a new alternative strategy for controlling the deleterious roles of these MMPs in breast cancer by inhibiting their upstream coregulator AIB1.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. Phone: (713) 798-6199. Fax: (713) 798-3017. E-mail: jxu{at}bcm.tmc.edu

{triangledown} Published ahead of print on 21 July 2008.

{dagger} L.Q. and L.L. contributed equally to this work.

Molecular and Cellular Biology, October 2008, p. 5937-5950, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00579-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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