PPARγ signaling exacerbates mammary gland tumor development
- Enrique Saez1,4,
- John Rosenfeld1,5,
- Antonia Livolsi2,
- Peter Olson3,
- Eleuterio Lombardo1,
- Michael Nelson1,
- Ester Banayo1,
- Robert D. Cardiff2,
- Juan Carlos Izpisua-Belmonte1, and
- Ronald M. Evans1,6
- 1The Salk Institute for Biological Studies, and Howard Hughes Medical Institute, La Jolla, California 92037, USA; 2Center for Comparative Medicine, Department of Pathology, University of California, Davis, California 95616, USA; 3Department of Biology, University of California, San Diego, La Jolla, California 92037, USA
Abstract
Breast cancer cell lines that express the nuclear peroxisome proliferator-activated receptor γ (PPARγ) can be prompted to undergo growth arrest and differentiation when treated with synthetic PPARγ ligands. To evaluate the therapeutic potential of increased PPARγ signaling in vivo, we generated transgenic mice that express a constitutively active form of PPARγ in mammary gland. These mice are indistinguishable from their wild-type littermates. However, when bred to a transgenic strain prone to mammary gland cancer, bigenic animals develop tumors with greatly accelerated kinetics. Surprisingly, in spite of their more malignant nature, bigenic tumors are more secretory and differentiated. The molecular basis of this tumor-promoting effect may be an increase in Wnt signaling, as ligand activation of PPARγ potentiates Wnt function in an in vivo model of this pathway. These results suggest that once an initiating event has taken place, increased PPARγ signaling serves as a tumor promoter in the mammary gland.
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Footnotes
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Supplemental material is available at http://www.genesdev.org.
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1167804.
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↵4 Present address: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA
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↵5 Present address: Department of Functional Genomics, Chemicon International, Temecula, California 92590, USA
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↵6 Corresponding author.
↵6 E-MAIL evans{at}salk.edu; FAX (858) 455-1349.
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- Accepted January 29, 2004.
- Received November 5, 2003.
- Cold Spring Harbor Laboratory Press
