title: Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition.
abstract: BACKGROUND
  ErbB2-positive breast cancer is characterized by highly aggressive phenotypes and reduced responsiveness to standard therapies. Although specific ErbB2-targeted therapies have been designed, only a small percentage of patients respond to these treatments and most of them eventually relapse. The existence of this population of particularly aggressive and non-responding or relapsing patients urges the search for novel therapies. The purpose of this study was to determine whether cannabinoids might constitute a new therapeutic tool for the treatment of ErbB2-positive breast tumors. We analyzed their antitumor potential in a well established and clinically relevant model of ErbB2-driven metastatic breast cancer: the MMTV-neu mouse. We also analyzed the expression of cannabinoid targets in a series of 87 human breast tumors.
  
  
  RESULTS
  Our results show that both Delta9-tetrahydrocannabinol, the most abundant and potent cannabinoid in marijuana, and JWH-133, a non-psychotropic CB2 receptor-selective agonist, reduce tumor growth, tumor number, and the amount/severity of lung metastases in MMTV-neu mice. Histological analyses of the tumors revealed that cannabinoids inhibit cancer cell proliferation, induce cancer cell apoptosis, and impair tumor angiogenesis. Cannabinoid antitumoral action relies, at least partially, on the inhibition of the pro-tumorigenic Akt pathway. We also found that 91% of ErbB2-positive tumors express the non-psychotropic cannabinoid receptor CB2.
  
  
  CONCLUSIONS
  Taken together, these results provide a strong preclinical evidence for the use of cannabinoid-based therapies for the management of ErbB2-positive breast cancer.
authors.affiliation: Dept, Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
authors.forename: María M
authors.initials: MM
authors.lastname: Caffarel
authors.forename: Clara
authors.initials: C
authors.lastname: Andradas
authors.forename: Emilia
authors.initials: E
authors.lastname: Mira
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pérez-Gómez
authors.forename: Camilla
authors.initials: C
authors.lastname: Cerutti
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
authors.forename: Juana M
authors.initials: JM
authors.lastname: Flores
authors.forename: Isabel
authors.initials: I
authors.lastname: García-Real
authors.forename: José
authors.initials: J
authors.lastname: Palacios
authors.forename: Santos
authors.initials: S
authors.lastname: Mañes
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzmán
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002186:Cannabinoids / Q000494:pharmacology*; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*
chemical_list: D002186:Cannabinoids; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D043885:Receptor, Cannabinoid, CB2; D018719:Erb-b2 Receptor Tyrosine Kinases