title: Crosstalk between HER2 signaling and angiogenesis in breast cancer: molecular basis, clinical applications and challenges.
abstract: OBJECTIVE
  Angiogenesis is an essential hallmark of cancer. Targeting angiogenesis has proven its efficacy in the modern therapeutic paradigm. HER2 positive breast cancer, in particular, is a challenging disease in which resistance to standard therapy has been attributed to parallel and downstream signaling cascades including angiogenesis. This review explores the molecular mechanisms underlying crosstalk between HER2 signaling and angiogenesis. It highlights the role of angiogenesis in the emerging resistance to anti-HER2 therapy. It surveys the current repertoire of clinical trials involving use of combination of anti-HER2 and antiangiogenic therapies. Finally, it entertains the hopes and challenges posed by this novel therapeutic approach.
  
  
  RESULTS
  HER2 signaling upregulates angiogenesis at different levels and by different mechanisms. A large number of clinical trials were conducted in attempt to exploit the potential benefit of the combination. Results of early phase trials were promising. However, in the late phase clinical trials, the AVEREL trial did not demonstrate a consistent benefit for bevacizumab in the HER2 positive breast cancer patient population. The BETH trial is ongoing and recruiting patients. Safety issues regarding cardiovascular toxicity of the combination have been already raised. Negative experience of dual EGFR and VEGF targeting in colon cancer cannot be overlooked.
  
  
  CONCLUSIONS
  Angiogenesis and HER2 signaling are closely related at the molecular level. Appraisal of efficacy of antiangiogenic therapies requires revisit of the current literature as well as following the results of ongoing trials.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, American University of Beirut Medical Center, Beirut, Lebanon.
authors.forename: Raafat S
authors.initials: RS
authors.lastname: Alameddine
authors.forename: Zaher K
authors.initials: ZK
authors.lastname: Otrock
authors.forename: Ahmad
authors.initials: A
authors.lastname: Awada
authors.forename: Ali
authors.initials: A
authors.lastname: Shamseddine
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases