title: Close and stable relationship between proliferation and a hypoxia metagene in aromatase inhibitor-treated ER-positive breast cancer.
abstract: OBJECTIVE
  The majority of breast cancer patients who have estrogen receptor positive (ER(+)) tumors whose proliferation is reduced after estrogen deprivation by aromatase inhibitors (AI). This study investigates any link between proliferation and hypoxia, a major determinant of tumor biology, and defines the effect of estrogen deprivation on hypoxia-associated genes.
  
  
  METHODS
  Genome-wide expression profiles were obtained from tumor biopsies from 81 ER(+) postmenopausal patients, before and after 2 weeks' anastrozole treatment. A hypoxia metagene was developed by identifying genes clustered with classical hypoxia-regulated genes, excluding those associated with proliferation. Proliferation was measured by Ki67 and a proliferation metagene derived from two published breast cancer data sets.
  
  
  RESULTS
  Hypoxia and proliferation metagenes were associated at baseline (Pearson correlation coefficient, r = 0.67, P < 10(-4)) and after 2 weeks (r = 0.71, P < 10(-4)). Hypoxia metagene at baseline was associated with 2-week Ki67 (r = 0.43, P = 0.0002) and more weakly with poor 2-week Ki67 change consistent with a weak association with AI resistance. Hypoxia metagene was significantly downregulated with AI. This downregulation was significantly associated with change in the proliferation metagene and with Ki67 but, importantly, not with the substantial change in expression of classical estrogen-dependent genes.
  
  
  CONCLUSIONS
  Hypoxia metagene is closely associated with proliferation before and after AI treatment. The downregulation of hypoxia metagene after AI therapy is most likely the result of changes in proliferation. There may be a weak effect of hypoxia metagene on de novo resistance to AIs. These findings are important to consider in coapplication of antiproliferative agents with antiangiogenic or antihypoxia agents.
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom. zara.ghazoui@icr.ac.uk
authors.forename: Zara
authors.initials: Z
authors.lastname: Ghazoui
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.forename: Anita K
authors.initials: AK
authors.lastname: Dunbier
authors.forename: Helen
authors.initials: H
authors.lastname: Anderson
authors.forename: Tim
authors.initials: T
authors.lastname: Dexter
authors.forename: Simone
authors.initials: S
authors.lastname: Detre
authors.forename: Janine
authors.initials: J
authors.lastname: Salter
authors.forename: Ian E
authors.initials: IE
authors.lastname: Smith
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Mitchell
authors.initials: M
authors.lastname: Dowsett
mesh_terms: D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000235:genetics; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006801:Humans; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D011237:Predictive Value of Tests; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D012680:Sensitivity and Specificity; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D000077384:Anastrozole