title: Differences in the transcriptional response to fulvestrant and estrogen deprivation in ER-positive breast cancer.
abstract: OBJECTIVE
  Endocrine therapies include aromatase inhibitors and the selective estrogen receptor (ER) downregulator fulvestrant. This study aimed to determine whether the reported efficacy of fulvestrant over anastrozole, and high- over low-dose fulvestrant, reflect distinct transcriptional responses.
  
  
  METHODS
  Global gene expression profiles from ERα-positive breast carcinomas before and during presurgical treatment with fulvestrant (n = 22) or anastrozole (n = 81), and corresponding in vitro models, were compared. Transcripts responding differently to fulvestrant and estrogen deprivation were identified and integrated using Gene Ontology, pathway and network analyses to evaluate their potential significance.
  
  
  RESULTS
  The overall transcriptional response to fulvestrant and estrogen deprivation was correlated (r = 0.61 in presurgical studies, r = 0.87 in vitro), involving downregulation of estrogen-regulated and proliferation-associated genes. The transcriptional response to fulvestrant was of greater magnitude than estrogen deprivation (slope = 0.62 in presurgical studies, slope = 0.63 in vitro). Comparative analyses identified 28 genes and 40 Gene Ontology categories affected differentially by fulvestrant. Seventeen fulvestrant-specific genes, including CAV1/2, SNAI2, and NRP1, associated with ERα, androgen receptor (AR), and TP53, in a network regulating cell cycle, death, survival, and tumor morphology. Eighteen genes responding differently to fulvestrant specifically predicted antiproliferative response to fulvestrant, but not anastrozole. Transcriptional effects of low-dose fulvestrant correlated with high-dose treatment, but were of lower magnitude (ratio = 0.29).
  
  
  CONCLUSIONS
  The transcriptional response to fulvestrant has much in common with estrogen deprivation, but is stronger with distinctions potentially attributable to arrest of estrogen-independent ERα activity and involvement of AR signaling. Genes responding differently to fulvestrant may have predictive utility. These data are consistent with the clinical efficacy of fulvestrant versus anastrozole and higher dosing regimens.
authors.affiliation: Academic Biochemistry, Royal Marsden Foundation Trust; Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London;
authors.forename: Neill
authors.initials: N
authors.lastname: Patani
authors.affiliation: Academic Biochemistry, Royal Marsden Foundation Trust; Department of Biochemistry, University of Otago, Dunedin, New Zealand;
authors.forename: Anita K
authors.initials: AK
authors.lastname: Dunbier
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London;
authors.forename: Helen
authors.initials: H
authors.lastname: Anderson
authors.affiliation: Academic Biochemistry, Royal Marsden Foundation Trust;
authors.forename: Zara
authors.initials: Z
authors.lastname: Ghazoui
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London;
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ribas
authors.affiliation: AstraZeneca, Macclesfield; Boehringer Ingelheim, Vienna, Austria; and.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Anderson
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London;
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Clinical Trials and Statistics Unit, Institute of Cancer Research, Sutton, United Kingdom;
authors.forename: Roger
authors.initials: R
authors.lastname: A'hern
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London;
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.affiliation: AstraZeneca, Macclesfield;
authors.forename: Justin
authors.initials: J
authors.lastname: Lindemann
authors.affiliation: AstraZeneca, Macclesfield;
authors.forename: Robert
authors.initials: R
authors.lastname: Wellings
authors.affiliation: AstraZeneca, Macclesfield;
authors.forename: Jill
authors.initials: J
authors.lastname: Walker
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Irene
authors.initials: I
authors.lastname: Kuter
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London;
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Martin
authors.affiliation: Academic Biochemistry, Royal Marsden Foundation Trust; Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London; Mitch.Dowsett@icr.ac.uk.
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D000077267:Fulvestrant; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D017698:Postmenopause; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D004967:Estrogens; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol