PMID- 15217513
OWN - NLM
STAT- MEDLINE
DCOM- 20041104
LR  - 20181113
IS  - 1465-542X (Electronic)
IS  - 1465-5411 (Print)
IS  - 1465-5411 (Linking)
VI  - 6
IP  - 4
DP  - 2004
TI  - Expression of hypoxia-inducible factor-1alpha and cell cycle proteins in invasive 
      breast cancer are estrogen receptor related.
PG  - R450-9
AB  - BACKGROUND: The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key 
      regulator of the cellular response to hypoxia. Previous studies showed that 
      concentrations of its subunit HIF-1alpha, as a surrogate for HIF-1 activity, are 
      increased during breast carcinogenesis and can independently predict prognosis in 
      breast cancer. During carcinogenesis, the cell cycle is progressively 
      deregulated, and proliferation rate is a strong prognostic factor in breast 
      cancer. In this study we undertook a detailed evaluation of the relationships 
      between HIF-1alpha and cell cycle-associated proteins. METHODS: In a 
      representative estrogen receptor (ER) group of 150 breast cancers, the expression 
      of HIF-1alpha, vascular endothelial growth factor, the ER, HER-2/neu, Ki-67, 
      cyclin A, cyclin D1, p21, p53, and Bcl-2 was investigated by 
      immunohistochemistry. RESULTS: High concentrations (5% or more) of HIF-1alpha 
      were associated with increased proliferation as shown by positive correlations 
      with Ki-67 (P < 0.001) and the late S-G2-phase protein cyclin A (P < 0.001), but 
      not with the G1-phase protein cyclin D1. High HIF-1alpha concentrations were also 
      strongly associated with p53 positivity (P < 0.001) and loss of Bcl-2 expression 
      (P = 0.013). No association was found between p21 and HIF-1alpha (P = 0.105) in 
      the whole group of patients. However, the subgroup of ER-positive cancers was 
      characterized by a strong positive association between HIF-1alpha and p21 (P = 
      0.023), and HIF-1alpha lacked any relation with proliferation. CONCLUSION: 
      HIF-1alpha overexpression is associated with increased proliferation, which might 
      explain the adverse prognostic impact of increased concentrations of HIF-1alpha 
      in invasive breast cancer. In ER-positive tumors, HIF-1alpha is associated with 
      p21 but not against proliferation. This shows the importance of further 
      functional analysis to unravel the role of HIF-1 in late cell cycle progression, 
      and the link between HIF-1, p21, and ER.
FAU - Bos, Reinhard
AU  - Bos R
AD  - Department of Pathology, VU University medical center, Amsterdam, The 
      Netherlands. reinhardbos@hotmail.com
FAU - van Diest, Paul J
AU  - van Diest PJ
FAU - van der Groep, Petra
AU  - van der Groep P
FAU - Shvarts, Avi
AU  - Shvarts A
FAU - Greijer, Astrid E
AU  - Greijer AE
FAU - van der Wall, Elsken
AU  - van der Wall E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20040609
PL  - England
TA  - Breast Cancer Res
JT  - Breast cancer research : BCR
JID - 100927353
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Receptors, Estrogen)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Breast Neoplasms/*genetics/*pathology
MH  - Carcinoma, Ductal, Breast/genetics
MH  - Cell Cycle Proteins/*genetics
MH  - Gene Expression Regulation, Neoplastic/*genetics
MH  - Genes, p53/genetics
MH  - Humans
MH  - Hypoxia
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Lymph Nodes/pathology
MH  - Neoplasm Invasiveness/genetics/pathology
MH  - Neoplasm Staging
MH  - Receptors, Estrogen/*genetics
MH  - Transcription Factors/*genetics
PMC - PMC468666
EDAT- 2004/06/26 05:00
MHDA- 2004/11/05 09:00
PMCR- 2004/06/09
CRDT- 2004/06/26 05:00
PHST- 2004/03/16 00:00 [received]
PHST- 2004/05/12 00:00 [accepted]
PHST- 2004/06/26 05:00 [pubmed]
PHST- 2004/11/05 09:00 [medline]
PHST- 2004/06/26 05:00 [entrez]
PHST- 2004/06/09 00:00 [pmc-release]
AID - bcr813 [pii]
AID - 10.1186/bcr813 [doi]
PST - ppublish
SO  - Breast Cancer Res. 2004;6(4):R450-9. doi: 10.1186/bcr813. Epub 2004 Jun 9.