title: Sox2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer.
abstract: Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR), has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y)-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5) expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways.
authors: Committee on Cancer Biology, The University of Chicago, Chicago, Illinois, United States of America.
authors: Steven
authors: S
authors: Kregel
authors: Kyle J
authors: KJ
authors: Kiriluk
authors: Alex M
authors: AM
authors: Rosen
authors: Yi
authors: Y
authors: Cai
authors: Edwin E
authors: EE
authors: Reyes
authors: Kristen B
authors: KB
authors: Otto
authors: Westin
authors: W
authors: Tom
authors: Gladell P
authors: GP
authors: Paner
authors: Russell Z
authors: RZ
authors: Szmulewitz
authors: Donald J
authors: DJ
authors: Vander Griend
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009570:Nitriles; D009919:Orchiectomy; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D001549:Benzamides; D009570:Nitriles; D012333:RNA, Messenger; D011944:Receptors, Androgen; D012097:Repressor Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D010669:Phenylthiohydantoin; C540278:enzalutamide