title: Acquired resistance to endocrine treatments is associated with tumor-specific molecular changes in patient-derived luminal breast cancer xenografts.
abstract: OBJECTIVE
  Patients with luminal breast cancer (LBC) often become endocrine resistant over time. We investigated the molecular changes associated with acquired hormonoresistances in patient-derived xenografts of LBC.
  
  
  METHODS
  Two LBC xenografts (HBCx22 and HBCx34) were treated with different endocrine treatments (ET) to obtain xenografts with acquired resistances to tamoxifen (TamR) and ovariectomy (OvaR). PI3K pathway activation was analyzed by Western blot analysis and IHC and responses to ET combined to everolimus were investigated in vivo. Gene expression analyses were performed by RT-PCR and Affymetrix arrays.
  
  
  RESULTS
  HBCx22 TamR xenograft was cross-resistant to several hormonotherapies, whereas HBCx22 OvaR and HBCx34 TamR exhibited a treatment-specific resistance profile. PI3K pathway was similarly activated in parental and resistant xenografts but the addition of everolimus did not restore the response to tamoxifen in TamR xenografts. In contrast, the combination of fulvestrant and everolimus induced tumor regression in vivo in HBCx34 TamR, where we found a cross-talk between the estrogen receptor (ER) and PI3K pathways. Expression of several ER-controlled genes and ER coregulators was significantly changed in both TamR and OvaR tumors, indicating impaired ER transcriptional activity. Expression changes associated with hormonoresistance were both tumor and treatment specific and were enriched for genes involved in cell growth, cell death, and cell survival.
  
  
  CONCLUSIONS
  PDX models of LBC with acquired resistance to endocrine therapies show a great diversity of resistance phenotype, associated with specific deregulations of ER-mediated gene transcription. These models offer a tool for developing anticancer therapies and to investigate the dynamics of resistance emerging during pharmacologic interventions. Clin Cancer Res; 20(16); 4314-25. ©2014 AACR.
authors.affiliation: Departments of Medical Oncology and Laboratory of Preclinical Investigation, Translational Research Department;
authors.forename: Paul
authors.initials: P
authors.lastname: Cottu
authors.affiliation: Genetics, Hospital, Institut Curie;
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department;
authors.forename: Franck
authors.initials: F
authors.lastname: Assayag
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department;
authors.forename: Rania
authors.initials: R
authors.lastname: El Botty
authors.affiliation: Pathology Department, National Veterinary School of Alfort, Maisons Alfort, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Chateau-Joubert
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department;
authors.forename: Aurélie
authors.initials: A
authors.lastname: Thuleau
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department;
authors.forename: Thomas
authors.initials: T
authors.lastname: Bagarre
authors.affiliation: Affymetrix Platform, Translational Research Department;
authors.forename: Benoit
authors.initials: B
authors.lastname: Albaud
authors.affiliation: Affymetrix Platform, Translational Research Department;
authors.forename: Audrey
authors.initials: A
authors.lastname: Rapinat
authors.affiliation: Affymetrix Platform, Translational Research Department;
authors.forename: David
authors.initials: D
authors.lastname: Gentien
authors.affiliation: Genosplice;
authors.forename: Pierre
authors.initials: P
authors.lastname: de la Grange
authors.affiliation: Bioinformatics Unit, Inserm U900 Mines ParisTech;
authors.forename: Vonick
authors.initials: V
authors.lastname: Sibut
authors.affiliation: Genetics, Hospital, Institut Curie;
authors.forename: Sophie
authors.initials: S
authors.lastname: Vacher
authors.affiliation: Genetics, Hospital, Institut Curie;
authors.forename: Rana
authors.initials: R
authors.lastname: Hatem
authors.affiliation: INRA, Phase Department; Pathology Department, National Veterinary School of Alfort, Maisons Alfort, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Servely
authors.affiliation: Pathology Department, National Veterinary School of Alfort, Maisons Alfort, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Fontaine
authors.affiliation: Departments of Medical Oncology and Laboratory of Preclinical Investigation, Translational Research Department;
authors.forename: Didier
authors.initials: D
authors.lastname: Decaudin
authors.affiliation: Departments of Medical Oncology and.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Pierga
authors.affiliation: Translational Research Department, Institut Curie, Paris, France; and.
authors.forename: Sergio
authors.initials: S
authors.lastname: Roman-Roman
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department; elisabetta.marangoni@curie.fr.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C506487:ESR1 protein, human