title: Modeling a lethal prostate cancer variant with small-cell carcinoma features.
abstract: OBJECTIVE
  Small-cell prostate carcinoma (SCPC) morphology predicts for a distinct clinical behavior, resistance to androgen ablation, and frequent but short responses to chemotherapy. We sought to develop model systems that reflect human SCPC and can improve our understanding of its biology.
  
  
  METHODS
  We developed a set of castration-resistant prostate carcinomas xenografts and examined their fidelity to their human tumors of origin. We compared the expression and genomic profiles of SCPC and large-cell neuroendocrine carcinoma (LCNEC) xenografts to those of typical prostate adenocarcinoma xenografts. Results were validated immunohistochemically in a panel of 60 human tumors.
  
  
  RESULTS
  The reported SCPC and LCNEC xenografts retain high fidelity to their human tumors of origin and are characterized by a marked upregulation of UBE2C and other mitotic genes in the absence of androgen receptor (AR), retinoblastoma (RB1), and cyclin D1 (CCND1) expression. We confirmed these findings in a panel of samples of CRPC patients. In addition, array comparative genomic hybridization of the xenografts showed that the SCPC/LCNEC tumors display more copy number variations than the adenocarcinoma counterparts. Amplification of the UBE2C locus and microdeletions of RB1 were present in a subset, but none displayed AR nor CCND1 deletions. The AR, RB1, and CCND1 promoters showed no CpG methylation in the SCPC xenografts.
  
  
  CONCLUSIONS
  Modeling human prostate carcinoma with xenografts allows in-depth and detailed studies of its underlying biology. The detailed clinical annotation of the donor tumors enables associations of anticipated relevance to be made. Future studies in the xenografts will address the functional significance of the findings.
authors.affiliation: Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Tzelepi
authors.forename: Jiexin
authors.initials: J
authors.lastname: Zhang
authors.forename: Jing-Fang
authors.initials: JF
authors.lastname: Lu
authors.forename: Brittany
authors.initials: B
authors.lastname: Kleb
authors.forename: Guanglin
authors.initials: G
authors.lastname: Wu
authors.forename: Xinhai
authors.initials: X
authors.lastname: Wan
authors.forename: Anh
authors.initials: A
authors.lastname: Hoang
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.forename: Kanishka
authors.initials: K
authors.lastname: Sircar
authors.forename: Nora M
authors.initials: NM
authors.lastname: Navone
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.forename: Shoudan
authors.initials: S
authors.lastname: Liang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.forename: Sankar N
authors.initials: SN
authors.lastname: Maity
authors.forename: Ana M
authors.initials: AM
authors.lastname: Aparicio
mesh_terms: D000368:Aged; D000818:Animals; D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D046888:Tissue Array Analysis; D014183:Transplantation, Heterologous