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Hypoxia-Inducible Factor-1 Is a Key Regulator of Metastasis in a Transgenic Model of Cancer Initiation and Progression

¹ Division of Biological Sciences, Molecular Biology Section, and ² Department of Molecular Pathology, School of Medicine, University of California, San Diego, La Jolla, California

Requests for reprints: Randall S. Johnson, Department of Biology, University of California, San Diego, La Jolla, CA 92093-0377. Phone: 858-822-0509; Fax: 858-534-5831; E-mail: rjohnson{at}biomail.ucsd.edu.

Adaptation to hypoxia is a critical step in tumor progression and is, in part, regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1). Xenograft models have been extensively used to characterize the role of HIF-1 in experimental cancers. Although these models provide an understanding of tumor growth at terminal stages of malignancy, they do not address tumor initiation or metastatic progression. To elucidate these roles, HIF-1 was conditionally deleted in the mammary epithelium of a transgenic mouse model for metastatic breast cancer. Conditional deletion of HIF-1 in the mammary epithelium resulted in delayed tumor onset and retarded tumor growth; this was correlated with decreased tumor cell proliferation. Tumors with conditional deletion of HIF-1 were also less vascular during early tumor progression. Perhaps most surprisingly, deletion of HIF-1 in the mammary epithelium resulted in decreased pulmonary metastasis. These results show that whereas HIF-1 is not required for the initiation of breast tumor growth or tumor cell metastasis, the transcriptional activity of HIF-1 is a significant positive regulator of tumor progression and metastatic potential. [Cancer Res 2007;67(2):563–72]

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