title: A basal stem cell signature identifies aggressive prostate cancer phenotypes.
abstract: Evidence from numerous cancers suggests that increased aggressiveness is accompanied by up-regulation of signaling pathways and acquisition of properties common to stem cells. It is unclear if different subtypes of late-stage cancer vary in stemness properties and whether or not these subtypes are transcriptionally similar to normal tissue stem cells. We report a gene signature specific for human prostate basal cells that is differentially enriched in various phenotypes of late-stage metastatic prostate cancer. We FACS-purified and transcriptionally profiled basal and luminal epithelial populations from the benign and cancerous regions of primary human prostates. High-throughput RNA sequencing showed the basal population to be defined by genes associated with stem cell signaling programs and invasiveness. Application of a 91-gene basal signature to gene expression datasets from patients with organ-confined or hormone-refractory metastatic prostate cancer revealed that metastatic small cell neuroendocrine carcinoma was molecularly more stem-like than either metastatic adenocarcinoma or organ-confined adenocarcinoma. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common between prostate small cell neuroendocrine carcinoma and primary prostate basal cells. Taken together, our data suggest that aggressive prostate cancer shares a conserved transcriptional program with normal adult prostate basal stem cells.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095;
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Smith
authors.affiliation: Center for Biomolecular Science and Engineering, University of California, Santa Cruz, CA 95064;
authors.forename: Artem
authors.initials: A
authors.lastname: Sokolov
authors.affiliation: Department of Biomolecular Engineering, University of California, Santa Cruz, CA 95064;
authors.forename: Vladislav
authors.initials: V
authors.lastname: Uzunangelov
authors.affiliation: Center for Biomolecular Science and Engineering, University of California, Santa Cruz, CA 95064;
authors.forename: Robert
authors.initials: R
authors.lastname: Baertsch
authors.affiliation: Department of Biomolecular Engineering, University of California, Santa Cruz, CA 95064;
authors.forename: Yulia
authors.initials: Y
authors.lastname: Newton
authors.affiliation: Department of Biomolecular Engineering, University of California, Santa Cruz, CA 95064;
authors.forename: Kiley
authors.initials: K
authors.lastname: Graim
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095;
authors.forename: Colleen
authors.initials: C
authors.lastname: Mathis
authors.affiliation: Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095;
authors.forename: Donghui
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Center for Biomolecular Science and Engineering, University of California, Santa Cruz, CA 95064; Department of Biomolecular Engineering, University of California, Santa Cruz, CA 95064; owenwitte@mednet.ucla.edu jstuart@ucsc.edu.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Stuart
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095 owenwitte@mednet.ucla.edu jstuart@ucsc.edu.
authors.forename: Owen N
authors.initials: ON
authors.lastname: Witte
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D042361:Mammary Glands, Human / Q000166:cytology; D009362:Neoplasm Metastasis; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors
keywords: RNA-seq; basal cell; neuroendocrine prostate cancer; prostate cancer; stem cell signature