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dc.contributor.authorTran, Maxine GB
dc.contributor.authorBibby, Becky AS
dc.contributor.authorYang, Lingjian
dc.contributor.authorLo, Franklin
dc.contributor.authorWarren, Anne
dc.contributor.authorShukla, Deepa
dc.contributor.authorOsborne, Michelle
dc.contributor.authorHadfield, James
dc.contributor.authorCarroll, Thomas
dc.contributor.authorStark, Rory
dc.contributor.authorScott, Helen
dc.contributor.authorRamos-Montoya, Antonio
dc.contributor.authorMassie, Charlie
dc.contributor.authorMaxwell, Patrick
dc.contributor.authorWest, Catharine ML
dc.contributor.authorMills, Ian G
dc.contributor.authorNeal, David E
dc.date.accessioned2020-07-14T23:30:19Z
dc.date.available2020-07-14T23:30:19Z
dc.date.issued2020-05-25
dc.identifier.issn1471-2407
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/307956
dc.description.abstractBACKGROUND: Therapeutic targeting of the androgen signaling pathway is a mainstay treatment for prostate cancer. Although initially effective, resistance to androgen targeted therapies develops followed by disease progression to castrate-resistant prostate cancer (CRPC). Hypoxia and HIF1a have been implicated in the development of resistance to androgen targeted therapies and progression to CRCP. The interplay between the androgen and hypoxia/HIF1a signaling axes was investigated. METHODS: In vitro stable expression of HIF1a was established in the LNCaP cell line by physiological induction or retroviral transduction. Tumor xenografts with stable expression of HIF1a were established in castrated and non-castrated mouse models. Gene expression analysis identified transcriptional changes in response to androgen treatment, hypoxia and HIF1a. The binding sites of the AR and HIF transcription factors were identified using ChIP-seq. RESULTS: Androgen and HIF1a signaling promoted proliferation in vitro and enhanced tumor growth in vivo. The stable expression of HIF1a in vivo restored tumor growth in the absence of endogenous androgens. Hypoxia reduced AR binding sites whereas HIF binding sites were increased with androgen treatment under hypoxia. Gene expression analysis identified seven genes that were upregulated both by AR and HIF1a, of which six were prognostic. CONCLUSIONS: The oncogenic AR, hypoxia and HIF1a pathways support prostate cancer development through independent signaling pathways and transcriptomic profiles. AR and hypoxia/HIF1a signaling pathways independently promote prostate cancer progression and therapeutic targeting of both pathways simultaneously is warranted.
dc.format.mediumElectronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectTumor Cells, Cultured
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectProstatic Neoplasms
dc.subjectAndrogen Antagonists
dc.subjectReceptors, Androgen
dc.subjectAndrogens
dc.subjectXenograft Model Antitumor Assays
dc.subjectGene Expression Profiling
dc.subjectSignal Transduction
dc.subjectApoptosis
dc.subjectCell Proliferation
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectMale
dc.subjectHypoxia-Inducible Factor 1, alpha Subunit
dc.subjectTranscriptional Activation
dc.subjectBiomarkers, Tumor
dc.subjectHypoxia
dc.titleIndependence of HIF1a and androgen signaling pathways in prostate cancer.
dc.typeArticle
prism.issueIdentifier1
prism.publicationDate2020
prism.publicationNameBMC Cancer
prism.startingPage469
prism.volume20
dc.identifier.doi10.17863/CAM.55048
dcterms.dateAccepted2020-04-22
rioxxterms.versionofrecord10.1186/s12885-020-06890-6
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2020-05-25
dc.contributor.orcidWarren, Anne [0000-0002-1170-7867]
dc.contributor.orcidStark, Rory [0000-0002-1790-5469]
dc.contributor.orcidMaxwell, Patrick [0000-0002-0338-2679]
dc.contributor.orcidMills, Ian G [0000-0001-5347-5083]
dc.identifier.eissn1471-2407
rioxxterms.typeJournal Article/Review
cam.issuedOnline2020-05-25


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International