Hypoxia and Hypoxia-Inducible Factor-1 Expression Enhance Osteolytic Bone Metastases of Breast Cancer
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Abstract
Hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. The transcription factor hypoxia-inducible factor-1 (HIF-1) is a major regulator of adaptation to hypoxia and is implicated in the malignant progression of cancers. Here, we studied whether hypoxia and HIF-1 expression contribute to the development of bone metastases using a well-characterized animal model of bone metastasis in MDA-MB-231 human breast cancer cells. To study the role of hypoxia in bone metastases, we tested the effects of the fusion protein (TOP3), the oxygen-dependent degradation domain of HIF-1α fused with HIV-TAT, and procaspase-3. TOP3 selectively induced apoptosis in hypoxic tumor cells in vitro and significantly reduced bone metastases in vivo. We next examined the role of HIF-1 in bone metastases by establishing MDA-MB-231 cells overexpressing constitutively active or dominant-negative HIF-1α (MDA/CA-HIF or MDA/DN-HIF, respectively). Bone metastases of MDA/CA-HIF were significantly increased with elevated number of CD31-positive blood vessels. In contrast, bone metastases were significantly reduced in MDA/DN-HIF. Because the progression of osteolytic bone metastases is due in part to the imbalance between bone formation and bone resorption, we examined the effects of hypoxia and HIF-1 on the differentiation of osteoblasts and osteoclasts. Hypoxia and CA-HIF overexpression markedly inhibited osteoblastic differentiation, whereas hypoxia increased osteoclast-like cell formation. In conclusion, these results suggest that tumor-associated hypoxia and HIF-1 expression promote the progression of bone metastases in breast cancer. Our results also suggest that hypoxia and HIF-1 lead to the development of osteolytic bone metastases by suppressing osteoblast differentiation and promoting osteoclastogenesis. [Cancer Res 2007;67(9):4157–63]
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Insights from a transgenic mouse model of metastatic breast cancer and xenograft models of breast cancer point to HIF-1α as a critical regulator of metastasis.
“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 Hiraga et al., 2007
Inactivation of HIF decreases the metastatic potential of tumor cells.
“whereas inactivation of HIF decreases the metastatic potential of tumor cells”
From Hypoxic control of metastasis (2016) · cites this paper as [43]
Overexpression of HIF in tumor cells promotes metastasis in experimental models.
“In experimental models, overexpression of HIF in tumor cells promotes metastasis”
From Hypoxic control of metastasis (2016) · cites this paper as [43]
Expression of a constitutively active or dominant negative form of HIF-1α increased or decreased, respectively, tumor area and blood vessel density in long bone sections after intracardiac injection of MDA-MB-231 cells.
“Compared to an empty vector subclone, expression of a constitutively active or dominant negative form of HIF-1α increased or decreased, respectively, the tumor area and blood vessel density in long bone sections [32].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [32]
Because breast cancer cells were injected directly into the circulation, the bone colonization studies do not provide compelling evidence that HIF-1 is required for spontaneous metastasis from breast to bone, as opposed to a more limited requirement for bone colonization by circulating tumor cells.
“Because BCCs were injected directly into the circulation, these studies do not provide compelling evidence that HIF-1 is required for spontaneous metastasis from breast to bone as opposed to a more limited requirement for bone colonization by circulating tumor cells.”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [32]
Bone metastases formed after injection of MDA-MB-231 cells contained hypoxic regions, and exposure of spleen cells to hypoxia in vitro inhibited osteoblast differentiation and stimulated osteoclast differentiation.
“The bone metastases that formed after injection of MDA-MB-231 cells contained hypoxic regions and exposure of spleen cells to hypoxia in vitro inhibited osteoblast differentiation and stimulated osteoclast differentiation [32].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [32]
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- Authors
- Hiraga, T., Kizaka-Kondoh, S., Hirota, K., Hiraoka, M., & Yoneda, T.
- Affiliations
- Matsumoto Dental University (JP)
- 3Department of Therapeutic Radiation Oncology, Kyoto University Graduate School of Medicine; and
- Kyoto University Hospital (JP)
- Kyoto University (JP)
- The University of Osaka (JP)
- Venue
- Cancer Research
- Published
- 2007-05-01
- Volume
- 67
- Issue
- 9
- Pages
- 4157-4163
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2047253593
- Cited by
- 242
- References
- 40
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 15 · 2022: 15 · 2021: 13 · 2020: 15 · 2019: 18 · 2018: 8 · 2017: 14 · 2016: 12 · 2015: 10 · 2014: 14 · 2013: 19 · 2012: 10
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Health Sciences › Medicine › Oncology › Bone health and treatments
- Keywords
- tumor hypoxia, HIF-1, HIF-1α, breast cancer bone metastasis, osteolytic bone metastasis, oxygen-dependent degradation domain, procaspase-3, apoptosis, tumor angiogenesis, osteogenic differentiation, osteoclastogenesis, bone resorption, MDA-MB-231 cells
- MeSH terms
- Animals, Bone Neoplasms, Breast Neoplasms, Female, Humans, Indazoles, Mice, Inbred C3H, Mice, Nude, Recombinant Fusion Proteins, Transfection, Cell Hypoxia, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Caspase 3
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