Cited by 242Cancer, Hypoxia, and MetabolismMechanisms of cancer metastasisBone health and treatments

The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.

Hypoxia and Hypoxia-Inducible Factor-1 Expression Enhance Osteolytic Bone Metastases of Breast Cancer

Hiraga, Toru, Kizaka-Kondoh, Shinae, Hirota, Kiichi, Hiraoka, Masahiro, Yoneda, Toshiyuki·2007·Cancer Research

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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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Nitric Oxide Induces Hypoxia-inducible Factor 1 Activation That Is Dependent on MAPK and Phosphatidylinositol 3-Kinase Signaling
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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)
ORCID: Hiraga, Toru
Hirota, Kiichi
Hiraoka, Masahiro
Yoneda, Toshiyuki
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2007-05-01
Volume: 67
Issue: 9
Pages: 4157-4163
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-06-2355
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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Hypoxia and Hypoxia-Inducible Factor-1 Expression Enhance Osteolytic Bone Metastases of Breast Cancer

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