title: Integrated genomics of ovarian xenograft tumor progression and chemotherapy response.
abstract: BACKGROUND
  Ovarian cancer is the most deadly gynecological cancer with a very poor prognosis. Xenograft mouse models have proven to be one very useful tool in testing candidate therapeutic agents and gene function in vivo. In this study we identify genes and gene networks important for the efficacy of a pre-clinical anti-tumor therapeutic, MT19c.
  
  
  METHODS
  In order to understand how ovarian xenograft tumors may be growing and responding to anti-tumor therapeutics, we used genome-wide mRNA expression and DNA copy number measurements to identify key genes and pathways that may be critical for SKOV-3 xenograft tumor progression. We compared SKOV-3 xenografts treated with the ergocalciferol derived, MT19c, to untreated tumors collected at multiple time points. Cell viability assays were used to test the function of the PPARγ agonist, Rosiglitazone, on SKOV-3 cell growth.
  
  
  RESULTS
  These data indicate that a number of known survival and growth pathways including Notch signaling and general apoptosis factors are differentially expressed in treated vs. untreated xenografts. As tumors grow, cell cycle and DNA replication genes show increased expression, consistent with faster growth. The steroid nuclear receptor, PPARγ, was significantly up-regulated in MT19c treated xenografts. Surprisingly, stimulation of PPARγ with Rosiglitazone reduced the efficacy of MT19c and cisplatin suggesting that PPARγ is regulating a survival pathway in SKOV-3 cells. To identify which genes may be important for tumor growth and treatment response, we observed that MT19c down-regulates some high copy number genes and stimulates expression of some low copy number genes suggesting that these genes are particularly important for SKOV-3 xenograft growth and survival.
  
  
  CONCLUSIONS
  We have characterized the time dependent responses of ovarian xenograft tumors to the vitamin D analog, MT19c. Our results suggest that PPARγ promotes survival for some ovarian tumor cells. We propose that a combination of regulated expression and copy number can identify genes that are likely important for chemotherapy response. Our findings suggest a new approach to identify candidate genes that are critical for anti-tumor therapy.
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women’s Oncology, Department of Obstetrics and Gynecology, Women and Infants7 Hospital, Alpert Medical School of Brown University, Providence, RI 02905, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Stuckey
authors.forename: Andrew
authors.initials: A
authors.lastname: Fischer
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Miller
authors.forename: Sara
authors.initials: S
authors.lastname: Hillenmeyer
authors.forename: Kyu K
authors.initials: KK
authors.lastname: Kim
authors.forename: Anna
authors.initials: A
authors.lastname: Ritz
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Raphael
authors.forename: Laurent
authors.initials: L
authors.lastname: Brard
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Brodsky
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D016000:Cluster Analysis; D004872:Ergocalciferols / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023281:Genomics / Q000379:methods*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D059467:Transcriptome; D047368:Tumor Burden / Q000187:drug effects; D014815:Vitamins / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004872:Ergocalciferols; C568376:MT19c compound; D047495:PPAR gamma; D045162:Thiazolidinediones; D014815:Vitamins; D000077154:Rosiglitazone; D002945:Cisplatin