title: Targeting CXCR1/2 significantly reduces breast cancer stem cell activity and increases the efficacy of inhibiting HER2 via HER2-dependent and -independent mechanisms.
abstract: OBJECTIVE
  Breast cancer stem-like cells (CSC) are an important therapeutic target as they are predicted to be responsible for tumor initiation, maintenance, and metastases. Interleukin (IL)-8 is upregulated in breast cancer and is associated with poor prognosis. Breast cancer cell line studies indicate that IL-8 via its cognate receptors, CXCR1 and CXCR2, is important in regulating breast CSC activity. We investigated the role of IL-8 in the regulation of CSC activity using patient-derived breast cancers and determined the potential benefit of combining CXCR1/2 inhibition with HER2-targeted therapy.
  
  
  METHODS
  CSC activity of metastatic and invasive human breast cancers (n = 19) was assessed ex vivo using the mammosphere colony-forming assay.
  
  
  RESULTS
  Metastatic fluid IL-8 level correlated directly with mammosphere formation (r = 0.652; P < 0.05; n = 10). Recombinant IL-8 directly increased mammosphere formation/self-renewal in metastatic and invasive breast cancers (n = 17). IL-8 induced activation of EGFR/HER2 and downstream signaling pathways and effects were abrogated by inhibition of SRC, EGFR/HER2, phosphoinositide 3-kinase (PI3K), or MEK. Furthermore, lapatinib, which targets EGFR/HER2, inhibited the mammosphere-promoting effect of IL-8 in both HER2-positive and negative patient-derived cancers. CXCR1/2 inhibition also blocked the effect of IL-8 on mammosphere formation and added to the efficacy of lapatinib in HER2-positive cancers.
  
  
  CONCLUSIONS
  These studies establish a role for IL-8 in the regulation of patient-derived breast CSC activity and show that IL-8/CXCR1/2 signaling is partly mediated via a novel SRC and EGFR/HER2-dependent pathway. Combining CXCR1/2 inhibitors with current HER2-targeted therapies has potential as an effective therapeutic strategy to reduce CSC activity in breast cancer and improve the survival of HER2-positive patients.
authors.affiliation: Breast Biology Group, Institute of Cancer Sciences, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.
authors.forename: Jagdeep K
authors.initials: JK
authors.lastname: Singh
authors.forename: Gillian
authors.initials: G
authors.lastname: Farnie
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Bundred
authors.forename: Bruno M
authors.initials: BM
authors.lastname: Simões
authors.forename: Amrita
authors.initials: A
authors.lastname: Shergill
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
authors.forename: Sacha J
authors.initials: SJ
authors.lastname: Howell
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clarke
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
chemical_list: D066246:ErbB Receptors; D016209:Interleukin-8; D018719:Erb-b2 Receptor Tyrosine Kinases; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B