title: FGFR signaling promotes the growth of triple-negative and basal-like breast cancer cell lines both in vitro and in vivo.
abstract: OBJECTIVE
  The oncogenic drivers of triple-negative (TN) and basal-like breast cancers are largely unknown. Substantial evidence now links aberrant signaling by the fibroblast growth factor receptors (FGFR) to the development of multiple cancer types. Here, we examined the role of FGFR signaling in TN breast cancer.
  
  
  METHODS
  We examined the sensitivity of a panel of 31 breast cancer cell lines to the selective FGFR inhibitor PD173074 and investigated the potential mechanisms underlying sensitivity.
  
  
  RESULTS
  TN breast cancer cell lines were more sensitive to PD173074 than comparator cell lines (P = 0.011), with 47% (7/15) of TN cell lines showing significantly reduced growth. The majority of TN cell lines showed only modest sensitivity to FGFR inhibition in two-dimensional growth but were highly sensitive in anchorage-independent conditions. PD173074 inhibited downstream mitogen-activated protein kinase and PI3K-AKT signaling and induced cell-cycle arrest and apoptosis. Basal-like breast cancer cell lines were found to express FGF2 ligand (11/21 positive) and, similarly, 62% of basal-like breast cancers expressed FGF2, as assessed by immunohistochemistry compared with 5% of nonbasal breast cancers (P < 0.0001). RNA interference targeting of FGF2 in basal-like cell lines significantly reduced growth in vitro and reduced down stream signaling, suggesting an autocrine FGF2 signaling loop. Treatment with PD173074 significantly reduced the growth of CAL51 basal-like breast cancer cell line xenografts in vivo.
  
  
  CONCLUSIONS
  Basal-like breast cancer cell lines, and breast cancers, express autocrine FGF2 and show sensitivity to FGFR inhibitors, identifying a potential novel therapeutic approach for these cancers.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Sharpe
authors.forename: Alex
authors.initials: A
authors.lastname: Pearson
authors.forename: Maria T
authors.initials: MT
authors.lastname: Herrera-Abreu
authors.forename: Damian
authors.initials: D
authors.lastname: Johnson
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Welti
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Reynolds
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Turner
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D018295:Neoplasms, Basal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D017468:Receptors, Fibroblast Growth Factor; D011980:Receptors, Progesterone; C115711:PD 173074