title: Potential upstream regulators of cannabinoid receptor 1 signaling in prostate cancer: a Bayesian network analysis of data from a tissue microarray.
abstract: BACKGROUND
  The endocannabinoid system regulates cancer cell proliferation, and in prostate cancer a high cannabinoid CB1 receptor expression is associated with a poor prognosis. Down-stream mediators of CB1 receptor signaling in prostate cancer are known, but information on potential upstream regulators is lacking.
  
  
  RESULTS
  Data from a well-characterized tumor tissue microarray were used for a Bayesian network analysis using the max-min hill-climbing method. In non-malignant tissue samples, a directionality of pEGFR (the phosphorylated form of the epidermal growth factor receptor) → CB1 receptors were found regardless as to whether the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) was included as a parameter. A similar result was found in the tumor tissue, but only when FAAH was included in the analysis. A second regulatory pathway, from the growth factor receptor ErbB2 → FAAH was also identified in the tumor samples. Transfection of AT1 prostate cancer cells with CB1 receptors induced a sensitivity to the growth-inhibiting effects of the CB receptor agonist CP55,940. The sensitivity was not dependent upon the level of receptor expression. Thus a high CB1 receptor expression alone does not drive the cells towards a survival phenotype in the presence of a CB receptor agonist.
  
  
  CONCLUSIONS
  The data identify two potential regulators of the endocannabinoid system in prostate cancer and allow the construction of a model of a dysregulated endocannabinoid signaling network in this tumor. Further studies should be designed to test the veracity of the predictions of the network analysis in prostate cancer and other solid tumors.
authors.affiliation: Department of Statistics, Umeå School of Business and Economics, Umeå University, Umeå, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Häggström
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Cipriano
authors.forename: Linus Plym
authors.initials: LP
authors.lastname: Forshell
authors.forename: Emma
authors.initials: E
authors.lastname: Persson
authors.forename: Peter
authors.initials: P
authors.lastname: Hammarsten
authors.forename: Nephi
authors.initials: N
authors.lastname: Stella
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fowler
mesh_terms: D000581:Amidohydrolases / Q000502:physiology; D001499:Bayes Theorem; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000502:physiology; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000473:pathology* / Q000503:physiopathology*; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology; D012189:Retrospective Studies; D015398:Signal Transduction / Q000502:physiology*; D046888:Tissue Array Analysis / Q000379:methods*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D066246:ErbB Receptors; D008562:Membrane Glycoproteins; D043884:Receptor, Cannabinoid, CB1; D018719:Erb-b2 Receptor Tyrosine Kinases; D000099252:Fatty Acid Amide Hydrolases; C484445:LRIG1 protein, human; C508053:ERBB2 protein, human
keywords: cannabinoid receptor; directed acyclic graph; epidermal growth factor; fatty acid amide hydrolase; prostate cancer