Ets2-Dependent Stromal Regulation of Mouse Mammary Tumors

Albert K. Man, Lawrence J.T. Young, John A. Tynan, Jacqueline Lesperance, Mikala Egeblad, Zena Werb, Craig A. Hauser, William J. Muller, Robert Cardiff, Robert G. Oshima

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Abstract

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 p21 Cip1 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.

Original languageEnglish (US)
Pages (from-to)8614-8625
Number of pages12
JournalMolecular and Cellular Biology
Volume23
Issue number23
DOIs
StatePublished - Dec 1 2003

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Vascular Endothelial Growth Factor A
Breast Neoplasms
Alleles
Matrix Metalloproteinase 9
Mitogen-Activated Protein Kinases
Macrophages
Phosphorylation
Polyomavirus Transforming Antigens
Matrix Metalloproteinase 3
Neoplasms
Polyomavirus
Gene Targeting
Threonine
Stromal Cells
Codon
Embryonic Development
Adipose Tissue
Peptide Hydrolases
Transcription Factors
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Man, A. K., Young, L. J. T., Tynan, J. A., Lesperance, J., Egeblad, M., Werb, Z., ... Oshima, R. G. (2003). Ets2-Dependent Stromal Regulation of Mouse Mammary Tumors. Molecular and Cellular Biology, 23(23), 8614-8625. https://doi.org/10.1128/MCB.23.23.8614-8625.2003

Ets2-Dependent Stromal Regulation of Mouse Mammary Tumors. / Man, Albert K.; Young, Lawrence J.T.; Tynan, John A.; Lesperance, Jacqueline; Egeblad, Mikala; Werb, Zena; Hauser, Craig A.; Muller, William J.; Cardiff, Robert; Oshima, Robert G.

In: Molecular and Cellular Biology, Vol. 23, No. 23, 01.12.2003, p. 8614-8625.

Research output: Contribution to journalArticle

Man, AK, Young, LJT, Tynan, JA, Lesperance, J, Egeblad, M, Werb, Z, Hauser, CA, Muller, WJ, Cardiff, R & Oshima, RG 2003, 'Ets2-Dependent Stromal Regulation of Mouse Mammary Tumors', Molecular and Cellular Biology, vol. 23, no. 23, pp. 8614-8625. https://doi.org/10.1128/MCB.23.23.8614-8625.2003
Man AK, Young LJT, Tynan JA, Lesperance J, Egeblad M, Werb Z et al. Ets2-Dependent Stromal Regulation of Mouse Mammary Tumors. Molecular and Cellular Biology. 2003 Dec 1;23(23):8614-8625. https://doi.org/10.1128/MCB.23.23.8614-8625.2003
Man, Albert K. ; Young, Lawrence J.T. ; Tynan, John A. ; Lesperance, Jacqueline ; Egeblad, Mikala ; Werb, Zena ; Hauser, Craig A. ; Muller, William J. ; Cardiff, Robert ; Oshima, Robert G. / Ets2-Dependent Stromal Regulation of Mouse Mammary Tumors. In: Molecular and Cellular Biology. 2003 ; Vol. 23, No. 23. pp. 8614-8625.
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