title: Estrogen receptor-α directly regulates the hypoxia-inducible factor 1 pathway associated with antiestrogen response in breast cancer.
abstract: A majority of breast cancers are driven by estrogen via estrogen receptor-α (ERα). Our previous studies indicate that hypoxia-inducible factor 1α (HIF-1α) cooperates with ERα in breast cancer cells. However, whether ERα is implicated in the direct regulation of HIF-1α and the role of HIF-1α in endocrine therapy response are unknown. In this study we found that a subpopulation of HIF-1α targets, many of them bearing both hypoxia response elements and estrogen response elements, are regulated by ERα in normoxia and hypoxia. Interestingly, the HIF-1α gene itself also bears an estrogen response element, and its expression is directly regulated by ERα. Clinical data revealed that expression of the HIF-1α gene or a hypoxia metagene signature is associated with a poor outcome to endocrine treatment in ERα(+) breast cancer. HIF-1α was able to confer endocrine therapy resistance to ERα(+) breast cancer cells. Our findings define, for the first time to our knowledge, a direct regulatory pathway between ERα and HIF-1α, which might modulate hormone response in treatment.
authors.affiliation: Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom; Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105; jun.yang2@stjude.org.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Alaa
authors.initials: A
authors.lastname: AlTahan
authors.affiliation: Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom;
authors.forename: Dylan T
authors.initials: DT
authors.lastname: Jones
authors.affiliation: Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom;
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.affiliation: Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom;
authors.forename: Esther
authors.initials: E
authors.lastname: Bridges
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Rodrigo B
authors.initials: RB
authors.lastname: Interiano
authors.affiliation: Department of Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Chunxu
authors.initials: C
authors.lastname: Qu
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Nathan
authors.initials: N
authors.lastname: Vogt
authors.affiliation: Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom;
authors.forename: Ji-Liang
authors.initials: JL
authors.lastname: Li
authors.affiliation: Genomics Group, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;
authors.forename: Dilair
authors.initials: D
authors.lastname: Baban
authors.affiliation: Genomics Group, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;
authors.forename: Jiannis
authors.initials: J
authors.lastname: Ragoussis
authors.affiliation: Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3NB, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Nicholson
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
authors.affiliation: Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom;
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D020847:Estrogen Receptor Modulators / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013629:Tamoxifen
keywords: ERα; HIF-1α; tamoxifen