title: Evidence for the presence of disease-perturbed networks in prostate cancer cells by genomic and proteomic analyses: a systems approach to disease.
abstract: Prostate cancer is initially responsive to androgen ablation therapy and progresses to androgen-unresponsive states that are refractory to treatment. The mechanism of this transition is unknown. A systems approach to disease begins with the quantitative delineation of the informational elements (mRNAs and proteins) in various disease states. We employed two recently developed high-throughput technologies, massively parallel signature sequencing (MPSS) and isotope-coded affinity tag, to gain a comprehensive picture of the changes in mRNA levels and more restricted analysis of protein levels, respectively, during the transition from androgen-dependent LNCaP (model for early-stage prostate cancer) to androgen-independent CL1 cells (model for late-stage prostate cancer). We sequenced >5 million MPSS signatures, obtained >142,000 tandem mass spectra, and built comprehensive MPSS and proteomic databases. The integrated mRNA and protein expression data revealed underlying functional differences between androgen-dependent and androgen-independent prostate cancer cells. The high sensitivity of MPSS enabled us to identify virtually all of the expressed transcripts and to quantify the changes in gene expression between these two cell states, including functionally important low-abundance mRNAs, such as those encoding transcription factors and signal transduction molecules. These data enable us to map the differences onto extant physiologic networks, creating perturbation networks that reflect prostate cancer progression. We found 37 BioCarta and 14 Kyoto Encyclopedia of Genes and Genomes pathways that are up-regulated and 23 BioCarta and 22 Kyoto Encyclopedia of Genes and Genomes pathways that are down-regulated in LNCaP cells versus CL1 cells. Our efforts represent a significant step toward a systems approach to understanding prostate cancer progression.
authors.affiliation: Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103, USA.
authors.forename: Biaoyang
authors.initials: B
authors.lastname: Lin
authors.forename: James T
authors.initials: JT
authors.lastname: White
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.forename: Angelita G
authors.initials: AG
authors.lastname: Utleg
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Yan
authors.forename: Eugene C
authors.initials: EC
authors.lastname: Yi
authors.forename: Paul
authors.initials: P
authors.lastname: Shannon
authors.forename: Irina
authors.initials: I
authors.lastname: Khrebtukova
authors.forename: Paul H
authors.initials: PH
authors.lastname: Lange
authors.forename: David R
authors.initials: DR
authors.lastname: Goodlett
authors.forename: Daixing
authors.initials: D
authors.lastname: Zhou
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Vasicek
authors.forename: Leroy
authors.initials: L
authors.lastname: Hood
mesh_terms: D045744:Cell Line, Tumor; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000145:classification* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D040901:Proteomics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
chemical_list: D009363:Neoplasm Proteins; D012333:RNA, Messenger