title: Trastuzumab and pertuzumab produce changes in morphology and estrogen receptor signaling in ovarian cancer xenografts revealing new treatment strategies.
abstract: OBJECTIVE
  The aim of this study was to investigate the antitumor effects of HER2-directed combination therapy in ovarian cancer xenograft models to evaluate their potential. The combinations of trastuzumab and pertuzumab, and trastuzumab and aromatase inhibitor therapy were investigated.
  
  
  METHODS
  The effects of trastuzumab, pertuzumab, and letrozole on growth response, apoptosis, morphology, and gene and protein expression were evaluated in the SKOV3 ovarian cancer cell line xenograft and a panel of five human ovarian xenografts derived directly from clinical specimens.
  
  
  RESULTS
  The combination of HER2-directed antibodies showed enhanced antitumor activity compared with single antibody therapy in the SKOV3 xenograft model. Apoptosis, morphology, and estrogen-regulated gene expression were modulated by these antibodies in both spatial and temporal manners. A panel of ovarian cancer xenografts showed differential growth responses to the combination of trastuzumab and pertuzumab. High HER2 expression and increasing HER3 protein expression on treatment were associated with growth response. In trastuzumab-treated SKOV3 tumors, there was a change in tumor morphology, with a reduction in frequency of estrogen receptor alpha (ERα)-negative clear cell areas. Trastuzumab, but not pertuzumab, increased expression of ERα in SKOV3 xenografts when analyzed by quantitative immunofluorescence. ERα and downstream signaling targets were modulated by trastuzumab alone and in combination. Trastuzumab enhanced the responsiveness of SKOV3 xenografts to letrozole when given in combination.
  
  
  CONCLUSIONS
  These data suggest that trastuzumab in combination with pertuzumab could be an effective approach in high HER2-expressing ovarian cancers and could also enhance sensitivity to endocrine therapy in ERα-positive ovarian cancer.
authors.affiliation: Division of Pathology and Edinburgh Breakthrough Research Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors.forename: Dana
authors.initials: D
authors.lastname: Faratian
authors.forename: Annelien J M
authors.initials: AJ
authors.lastname: Zweemer
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nagumo
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sims
authors.forename: Morwenna
authors.initials: M
authors.lastname: Muir
authors.forename: Michael
authors.initials: M
authors.lastname: Dodds
authors.forename: Peter
authors.initials: P
authors.lastname: Mullen
authors.forename: Inhwa
authors.initials: I
authors.lastname: Um
authors.forename: Charlene
authors.initials: C
authors.lastname: Kay
authors.forename: Max
authors.initials: M
authors.lastname: Hasmann
authors.forename: David J
authors.initials: DJ
authors.lastname: Harrison
authors.forename: Simon P
authors.initials: SP
authors.lastname: Langdon
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D047072:Aromatase Inhibitors / Q000494:pharmacology; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018740:Genetic Heterogeneity; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000068878:Trastuzumab; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D000068878:Trastuzumab; C485206:pertuzumab