title: Altered expression of farnesyl pyrophosphate synthase in prostate cancer: evidence for a role of the mevalonate pathway in disease progression?
abstract: BACKGROUND
  Preclinical studies demonstrated effects of drugs inhibiting the mevalonate pathway including nitrogen-containing bisphosphonates (N-BPs) and statins on tumor growth and progression. The exact role of this pathway in prostate cancer (PC) has not been identified yet. Herein, we evaluate the expression of farnesyl pyrophosphate synthase (FPPS), the key enzyme of the mevalonate pathway, in PC.
  
  
  METHODS
  Prostate cancer (PC) and benign prostate tissue of 114 men who underwent radical prostatectomy were constructed to a tissue microarray. Immunohistochemical staining of FPPS was quantified by the Remmele/Stegner immunoreactivity-score. Patients' clinical follow-up was assessed. IRS was correlated to pathological and clinical data. The impact of FPPS expression on clinical course was assessed univariate and multivariate.
  
  
  RESULTS
  Mean IRS in PC and benign tissue was 5.7 (95% CI 5.0-6.5) and 2.6 (2.1-3.0, p < 0.0001). Mean IRS in PC tissue of patients with organ-confined and locally advanced disease (pT ≥ 3) was 5.09 (4.22-5.96) and 6.87 (5.57-8.17, p = 0.035). IRS of PC tissue significantly correlated with Gleason score (p = 0.03). Patients with PC tissue IRS >3 showed shorter recurrence-free survival compared to the remaining (p = 0.01). Increased FPPS expression is an independent risk factor for early biochemical recurrence (p = 0.032).
  
  
  CONCLUSIONS
  This is the first study on FPPS in PC specimens. The association of FPPS with established histopathological risk parameters and biochemical recurrence implicates a contribution of the mevalonate pathway to PC progression. Further functional analysis is required to explore the role of this pathway in PC and to investigate whether FPPS expression affects the response of PC cells to N-BPs.
authors.affiliation: Department of Urology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Todenhöfer
authors.forename: Jörg
authors.initials: J
authors.lastname: Hennenlotter
authors.forename: Ursula
authors.initials: U
authors.lastname: Kühs
authors.forename: Valentina
authors.initials: V
authors.lastname: Gerber
authors.forename: Georgios
authors.initials: G
authors.lastname: Gakis
authors.forename: Ulrich
authors.initials: U
authors.lastname: Vogel
authors.forename: Stefan
authors.initials: S
authors.lastname: Aufderklamm
authors.forename: Axel
authors.initials: A
authors.lastname: Merseburger
authors.forename: Judith
authors.initials: J
authors.lastname: Knapp
authors.forename: Arnulf
authors.initials: A
authors.lastname: Stenzl
authors.forename: Christian
authors.initials: C
authors.lastname: Schwentner
mesh_terms: D000368:Aged; D018450:Disease Progression; D018572:Disease-Free Survival; D051228:Geranyltranstransferase / Q000378:metabolism*; D006801:Humans; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism*; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011467:Prostate / Q000201:enzymology* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D012307:Risk Factors; D046888:Tissue Array Analysis
chemical_list: D051228:Geranyltranstransferase; D008798:Mevalonic Acid