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Hypoxia-Inducible Factor-1α Is a Key Regulator of Metastasis in a Transgenic Model of Cancer Initiation and Progression
Abstract
Adaptation to hypoxia is a critical step in tumor progression and is, in part, regulated by the transcription factor hypoxia-inducible factor-1α (HIF-1α). Xenograft models have been extensively used to characterize the role of HIF-1α 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-1α was conditionally deleted in the mammary epithelium of a transgenic mouse model for metastatic breast cancer. Conditional deletion of HIF-1α 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-1α were also less vascular during early tumor progression. Perhaps most surprisingly, deletion of HIF-1α in the mammary epithelium resulted in decreased pulmonary metastasis. These results show that whereas HIF-1α is not required for the initiation of breast tumor growth or tumor cell metastasis, the transcriptional activity of HIF-1α is a significant positive regulator of tumor progression and metastatic potential. [Cancer Res 2007;67(2):563–72]
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“Insights from a transgenic mouse model of metastatic breast cancer (Liao et al., 2007) and xenograft models of breast cancer (Hiraga et al., 2007;Lu et al., 2010) also point to HIF-1α as a critical regulator of metastasis.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Liao et al., 2007
In the citing paper
“whereas inactivation of HIF decreases the metastatic potential of tumor cells”
From Hypoxic control of metastasis (2016) · cites this paper as [46]
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The role of VEGF in cancer-induced angiogenesis and research progress of drugs targeting VEGF
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“Specifically, conditional knockout of HIF-1α in the mammary epithelium of MMTV-PyMT mice significantly inhibits formation of lung metastases but has less effect on growth of the primary mammary tumor (85).”
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“The significance of the contribution of HIF-1 to tumor growth is well documented [10 13], and mouse xenograft studies have clearly demonstrated that the inhibition of HIF-1 activity suppresses tumor growth [6, 11, 14].”
BackgroundThe tumour suppressor C/EBPδ inhibits FBXW7 expression and promotes mammary tumour metastasis
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“Mice deficient in mammary epithelial expression of HIF-1a exhibit reduced tumour growth and significantly fewer lung metastases (Liao et al, 2007).”
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BackgroundTargeting Hypoxia-Inducible Factor-1-Mediated Metastasis for Cancer Therapy
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“For example, Hif1a, a hypoxia inducible transcriptional factor has essential roles in cellular metabolism, angiogenesis, and also in tumor initiation and metastasis [32].”
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“Conversely, conditional depletion of HIF1α in the mammary epithelium of a transgenic mouse model for metastatic breast cancer decreases pulmonary metastasis [64].”
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“Furthermore, murine mammary tumour cells from mice with Cre-loxP-mediated inactivation of HIF-1a failed to reach the logarithmic growth phase under low oxygen conditions (Liao et al, 2007).”
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Self-citationAdiponectin Deficiency Limits Tumor Vascularization in the MMTV-PyV-mT Mouse Model of Mammary Cancer
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“When HIF-1a is conditionally deleted in the mammary epithelium of transgenic mice that are engineered to develop breast cancer, onset and growth of breast cancer are delayed and metastasis is decreased ( 27 ).”
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Metadata
- Authors
- Liao, D., Corle, C., Seagroves, T. N., & Johnson, R. S.
- Affiliations
- University of California San Diego (US)
- 1Division of Biological Sciences, Molecular Biology Section, and
- Venue
- Cancer Research
- Published
- 2007-01-15
- Volume
- 67
- Issue
- 2
- Pages
- 563-572
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2167510293
- Cited by
- 339
- References
- 38
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 17 · 2021: 20 · 2020: 13 · 2019: 14 · 2018: 14 · 2017: 14 · 2016: 17 · 2015: 26 · 2014: 21 · 2013: 25 · 2012: 29
- FWCI
- 10.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA082515, CA 082515)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- hypoxia-inducible factor-1α, metastasis, breast cancer, tumor initiation, tumor progression, mammary epithelium, conditional gene deletion, transgenic mouse model, tumor hypoxia, tumor cell proliferation, tumor vascularization, lung metastasis
- MeSH terms
- Animals, Female, Hyperplasia, Lung Neoplasms, Male, Mammary Neoplasms, Experimental, Mice, Transgenic, Neoplasm Metastasis, Transcription, Genetic, Mammary Neoplasms, Animal, Mice, Knockout, Disease Progression, Cell Growth Processes, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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