PMID- 17483326
OWN - NLM
STAT- MEDLINE
DCOM- 20070618
LR  - 20070507
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 9
DP  - 2007 May 1
TI  - Hypoxia and hypoxia-inducible factor-1 expression enhance osteolytic bone 
      metastases of breast cancer.
PG  - 4157-63
AB  - 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-1alpha 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-1alpha (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.
FAU - Hiraga, Toru
AU  - Hiraga T
AD  - Department of Biochemistry, Graduate School of Dentistry, Osaka University, 
      Suita, Osaka, Japan.
FAU - Kizaka-Kondoh, Shinae
AU  - Kizaka-Kondoh S
FAU - Hirota, Kiichi
AU  - Hirota K
FAU - Hiraoka, Masahiro
AU  - Hiraoka M
FAU - Yoneda, Toshiyuki
AU  - Yoneda T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Indazoles)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (TOP3 fusion protein)
RN  - 154453-18-6 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
MH  - Animals
MH  - Bone Neoplasms/genetics/*metabolism/*secondary
MH  - Breast Neoplasms/genetics/*metabolism/*pathology
MH  - Caspase 3/metabolism
MH  - Cell Hypoxia/physiology
MH  - Cell Line, Tumor
MH  - Female
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*biosynthesis/genetics
MH  - Indazoles/pharmacology
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Mice, Nude
MH  - Recombinant Fusion Proteins/metabolism/pharmacology
MH  - Transfection
EDAT- 2007/05/08 09:00
MHDA- 2007/06/19 09:00
CRDT- 2007/05/08 09:00
PHST- 2007/05/08 09:00 [pubmed]
PHST- 2007/06/19 09:00 [medline]
PHST- 2007/05/08 09:00 [entrez]
AID - 67/9/4157 [pii]
AID - 10.1158/0008-5472.CAN-06-2355 [doi]
PST - ppublish
SO  - Cancer Res. 2007 May 1;67(9):4157-63. doi: 10.1158/0008-5472.CAN-06-2355.