title: Identification of chemokine receptors as potential modulators of endocrine resistance in oestrogen receptor-positive breast cancers.
abstract: BACKGROUND
  Endocrine therapies target oestrogenic stimulation of breast cancer (BC) growth, but resistance remains problematic. Our aims in this study were (1) to identify genes most strongly associated with resistance to endocrine therapy by intersecting global gene transcription data from patients treated presurgically with the aromatase inhibitor anastrazole with those from MCF7 cells adapted to long-term oestrogen deprivation (LTED) (2) to assess the clinical value of selected genes in public clinical data sets and (3) to determine the impact of targeting these genes with novel agents.
  
  
  METHODS
  Gene expression and Ki67 data were available from 69 postmenopausal women with oestrogen receptor-positive (ER+) early BC, at baseline and 2 weeks after anastrazole treatment, and from cell lines adapted to LTED. The functional consequences of target genes on proliferation, ER-mediated transcription and downstream cell signalling were assessed.
  
  
  RESULTS
  By intersecting genes predictive of a poor change in Ki67 with those upregulated in LTED cells, we identified 32 genes strongly correlated with poor antiproliferative response that were associated with inflammation and/or immunity. In a panel of LTED cell lines, C-X-C chemokine receptor type 7 (CXCR7) and CXCR4 were upregulated compared to their wild types (wt), and CXCR7, but not CXCR4, was associated with reduced relapse-free survival in patients with ER+ BC. The CXCR4 small interfering RNA variant (siCXCR4) had no specific effect on the proliferation of wt-SUM44, wt-MCF7 and their LTED derivatives. In contrast, siCXCR7, as well as CCX733, a CXCR7 antagonist, specifically suppressed the proliferation of MCF7-LTED cells. siCXCR7 suppressed proteins associated with G1/S transition and inhibited ER transactivation in MCF7-LTED, but not wt-MCF7, by impeding association between ER and proline-, glutamic acid- and leucine-rich protein 1, an ER coactivator.
  
  
  CONCLUSIONS
  These data highlight CXCR7 as a potential therapeutic target warranting clinical investigation in endocrine-resistant BC.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ribas
authors.forename: Zara
authors.initials: Z
authors.lastname: Ghazoui
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gao
authors.forename: Sunil
authors.initials: S
authors.lastname: Pancholi
authors.forename: Aradhana
authors.initials: A
authors.lastname: Rani
authors.forename: Anita
authors.initials: A
authors.lastname: Dunbier
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Martin
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D047072:Aromatase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D010766:Phosphorylation; D017698:Postmenopause; D011499:Protein Processing, Post-Translational; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C501896:ACKR3 protein, human; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D054387:Receptors, CXCR; D011960:Receptors, Estrogen