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Molecular and Cellular Biology, December 2003, p. 8614-8625, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8614-8625.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Ets2-Dependent Stromal Regulation of Mouse Mammary Tumors

Albert K. Man,1,2,{dagger} Lawrence J. T. Young,3 John A. Tynan,1,2 Jacqueline Lesperance,1 Mikala Egeblad,4 Zena Werb,4 Craig A. Hauser,1 William J. Muller,5 Robert D. Cardiff,3 and Robert G. Oshima1,2*

The Burnham Institute, La Jolla, California 92037,1 Molecular Pathology Program, University of California at San Diego, La Jolla, California 92093,2 Pathology Department, University of California, Davis, California 95616,3 Department of Anatomy and Comprehensive Cancer Center, University of California, San Francisco, California 94143,4 Molecular Oncology Group, Departments of Medicine and Biochemistry, McGill University, Montreal, Quebec, Canada H3A 1A15

Received 1 November 2002/ Returned for modification 18 February 2003/ Accepted 25 August 2003

The Ets2 transcription factor is regulated by mitogen-activated protein (MAP) kinase phosphorylation of a single threonine residue. We generated by gene targeting a single codon mutation in Ets2 substituting Ala for the critical Thr-72 phosphorylation site (Ets2A72), to investigate the importance of MAP kinase activation of Ets2 in embryo and tumor development. Ets2A72/A72 mice are viable and develop normally. However, combining the Ets2A72 allele with a deletion mutant of Ets2 results in lethality at E11.5 and shows that Ets2A72 is a hypomorphic allele. Mammary tumors caused by transgenic polyomavirus middle T antigen, activated Neu(Erbb2), or the combination of Neu and transgenic VEGF (Neu; VEGF-25) were all restricted in Ets2A72/A72 females. The Ets2A72/A72 restriction on Neu; VEGF-25 tumor growth was associated with increased p21Cip1 expression. The size of tumors transplanted into fat pads of mice with Ets2 targeted alleles was correlated directly with Ets2 activity and fewer stromal cells expressing matrix metalloproteinase 9 (MMP-9). Decreased MMP-3 and MMP-9 mRNAs were confirmed in Ets2A72/A72 macrophages. Activation of Ets2 at Thr-72 acts in the stroma, downstream of vascular endothelial growth factor production, in part through the regulation of macrophage proteases to support the progression of Neu- and polyomavirus middle-T-initiated mammary tumors.

* Corresponding author: The Burnham Institute, 10901 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 646-3147. Fax: (858) 713-6268. E-mail: rgoshima{at}burnham.org.

{dagger} Present address: Prediction Sciences, San Diego, CA 92116.

Molecular and Cellular Biology, December 2003, p. 8614-8625, Vol. 23, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.23.8614-8625.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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