PMID- 21897387
OWN - NLM
STAT- MEDLINE
DCOM- 20111129
LR  - 20211203
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 105
IP  - 7
DP  - 2011 Sep 27
TI  - Rapid non-genomic signalling by 17beta-oestradiol through c-Src involves 
      mTOR-dependent expression of HIF-1alpha in breast cancer cells.
PG  - 953-60
LID - 10.1038/bjc.2011.349 [doi]
AB  - BACKGROUND: Hypoxia-inducible factor 1 (HIF1) has been implicated in regulating 
      many of the genes responsible for angiogenesis, erythropoiesis, glucose 
      metabolism and cancer pathogenesis. In this study, we demonstrate that exposure 
      of human breast cancer lines to 17beta-oestradiol (E2) rapidly induced the 
      expression of HIF-1alpha, the regulated subunit of HIF1, in normoxic condition. 
      Hypoxia-inducible factor-1alpha is normally degraded in normoxia through 
      ubiquitination-mediated proteolysis, whereas hypoxia modulates HIF-1alpha level by 
      inhibiting ubiquitination-mediated degradation. METHODS: Oestradiol-induced 
      accumulation of HIF-1alpha in breast cancer lines was detected by western blot 
      analysis and its promoter activity was measured by HIF1 reporter assay. Molecular 
      signalling of oestradiol-mediated HIF-1alpha expression was studied using specific 
      pharmacological inhibitors and small interference RNA by co-immunoprecipitation 
      and western blotting analysis. RESULTS: Oestradiol has been observed to rapidly 
      activate the nongenomic signalling cascade leading to HIF-1alpha protein synthesis. 
      The results define a signalling pathway in breast cancer cells whereby oestradiol 
      induces a rapid protein-protein interaction of ERalpha-c-Src-PI3K, resulting in the 
      activation of PI3K/AKT pathway leading to mammalian target of rapamycin (mTOR) 
      phosphorylation. The mTOR then stimulates translation by phosphorylating p70 S6 
      kinase and 4EB-P1, modulating HIF-1alpha protein synthesis. Oestradiol-stimulated 
      HIF-1alpha activity was inhibited by either siRNA or pharmacological inhibitors to 
      ERalpha, c-Src, PI3K and mTOR, providing a mechanism for the modulation of HIF-1alpha 
      protein synthesis. CONCLUSION: These results show oestradiol-induced expression 
      of HIF-1alpha, downstream of the ERalpha/c-Src/PI3K/AKT/mTOR pathway in human breast 
      cancer cells.
FAU - Sudhagar, S
AU  - Sudhagar S
AD  - Centre for Biotechnology, Anna University, Chennai 600025, India.
FAU - Sathya, S
AU  - Sathya S
FAU - Lakshmi, B S
AU  - Lakshmi BS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110906
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Small Interfering)
RN  - 4TI98Z838E (Estradiol)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (CSK Tyrosine-Protein Kinase)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.10.23 (CSK protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Blotting, Western
MH  - Breast Neoplasms/*drug therapy/*metabolism/pathology
MH  - CSK Tyrosine-Protein Kinase
MH  - Estradiol/*pharmacology
MH  - Female
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*genetics/*metabolism
MH  - Immunoprecipitation
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Promoter Regions, Genetic/genetics
MH  - Protein-Tyrosine Kinases/antagonists & inhibitors/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/genetics/metabolism
MH  - RNA, Small Interfering/genetics
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Tumor Cells, Cultured
MH  - src-Family Kinases
PMC - PMC3185958
COIS- The authors declare no conflict of interest.
EDAT- 2011/09/08 06:00
MHDA- 2011/12/13 00:00
PMCR- 2012/09/27
CRDT- 2011/09/08 06:00
PHST- 2011/09/08 06:00 [entrez]
PHST- 2011/09/08 06:00 [pubmed]
PHST- 2011/12/13 00:00 [medline]
PHST- 2012/09/27 00:00 [pmc-release]
AID - bjc2011349 [pii]
AID - 10.1038/bjc.2011.349 [doi]
PST - ppublish
SO  - Br J Cancer. 2011 Sep 27;105(7):953-60. doi: 10.1038/bjc.2011.349. Epub 2011 Sep 
      6.