title: Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence.
abstract: BACKGROUND
  We reported that Notch-1, a potent breast oncogene, is activated in response to trastuzumab and contributes to trastuzumab resistance in vitro. We sought to determine the preclinical benefit of combining a Notch inhibitor (γ-secretase inhibitor (GSI)) and trastuzumab in both trastuzumab-sensitive and trastuzumab-resistant, ErbB-2-positive, BT474 breast tumours in vivo. We also studied if the combination therapy of lapatinib plus GSI can induce tumour regression of ErbB-2-positive breast cancer.
  
  
  METHODS
  We generated orthotopic breast tumour xenografts from trastuzumab- or lapatinib-sensitive and trastuzumab-resistant BT474 cells. We investigated the antitumour activities of two distinct GSIs, LY 411 575 and MRK-003, in vivo.
  
  
  RESULTS
  Our findings showed that combining trastuzumab plus a GSI completely prevented (MRK-003 GSI) or significantly reduced (LY 411 575 GSI) breast tumour recurrence post-trastuzumab treatment in sensitive tumours. Moreover, combining lapatinib plus MRK-003 GSI showed significant reduction of tumour growth. Furthermore, a GSI partially reversed trastuzumab resistance in resistant tumours.
  
  
  CONCLUSIONS
  Our data suggest that a combined inhibition of Notch and ErbB-2 signalling pathways could decrease recurrence rates for ErbB-2-positive breast tumours and may be beneficial in the treatment of recurrent trastuzumab-resistant disease.
authors.affiliation: Molecular Biology Program, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA.
authors.forename: K
authors.initials: K
authors.lastname: Pandya
authors.forename: K
authors.initials: K
authors.lastname: Meeke
authors.forename: A G
authors.initials: AG
authors.lastname: Clementz
authors.forename: A
authors.initials: A
authors.lastname: Rogowski
authors.forename: J
authors.initials: J
authors.lastname: Roberts
authors.forename: L
authors.initials: L
authors.lastname: Miele
authors.forename: K S
authors.initials: KS
authors.lastname: Albain
authors.forename: C
authors.initials: C
authors.lastname: Osipo
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D045744:Cell Line, Tumor; D003499:Cyclic S-Oxides / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D018390:Gene Targeting; D018815:Genes, erbB; D018734:Genes, erbB-2; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000235:genetics; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects*; D013830:Thiadiazoles / Q000494:pharmacology; D000068878:Trastuzumab
chemical_list: D053829:Amyloid Precursor Protein Secretases; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003499:Cyclic S-Oxides; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D051880:Receptors, Notch; D013830:Thiadiazoles; D000068878:Trastuzumab; C523799:MRK 003