title: Overexpression of ERβ is sufficient to inhibit hypoxia-inducible factor-1 transactivation.
abstract: Estrogen receptor (ER) β is predicted to play an important role in the prevention of breast cancer development and progression. We have previously shown that ERβ suppresses hypoxia inducible factor (HIF)-1-mediated transcription through aryl hydrocarbon receptor nuclear translocator (ARNT) degradation via ubiquitination processes. In this study, we attempted to examine the effect of ERβ specific ligand on HIF-1 inhibition in ERβ positive PC3 cells and ERβ transfected MCF-7 cells. ERβ specific agonist diarylpropionitrile (DPN) stimulated estrogen response element (ERE)-luciferase activity in a similar fashion to estradiol in PC3 cells. We observed that DPN down-regulates the ARNT protein levels leading to an attenuation of hypoxia-induced hypoxia response element (HRE)-driven luciferase reporter gene activation in PC3 cells. Treatment of DPN reduced vascular endothelial growth factor (VEGF) expression and co-treatment with ERβ specific antagonist PHTPP abrogated the effect in PC3 cells. We then examined the effect of DPN in ERβ transfected MCF-7 cells. HIF-1 transcriptional activity repression by ERβ was not further reduced by DPN, as examined by HRE-driven luciferase assays. Expression of ERβ significantly decreased VEGF secretion and ARNT expression under hypoxic conditions. However, DPN did not additionally affect this suppression in MCF-7 cells transfected with ERβ. This result shows that unliganded ERβ is sufficient to inhibit HIF-1 in systems of overexpression.
authors.affiliation: Department of Bioscience and Biotechnology, College of Life Science, Institute of Biotechnology, Sejong University, Kwangjingu, Kunjadong, Seoul 143-747, Republic of Korea.
authors.forename: Choa
authors.initials: C
authors.lastname: Park
authors.affiliation: Department of Bioscience and Biotechnology, College of Life Science, Institute of Biotechnology, Sejong University, Kwangjingu, Kunjadong, Seoul 143-747, Republic of Korea. Electronic address: yjlee@sejong.ac.kr.
authors.forename: YoungJoo
authors.initials: Y
authors.lastname: Lee
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D047629:Estrogen Receptor beta / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D010100:Oxygen / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D047629:Estrogen Receptor beta; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen
keywords: Estrogen receptor beta; Hypoxia; Hypoxia-inducible factor-1