title: The influence of growth hormone/insulin-like growth factor deficiency on prostatic dysplasia in pbARR2-Cre, PTEN knockout mice.
abstract: BACKGROUND
  Elevated insulin-like growth factor-I (IGF-I) serum levels and phosphatase and tensin homolog (PTEN) loss are prostate cancer (PCa) risk factors that enhance androgen-responsive and castration-resistant PCa xenografts growth.
  
  
  METHODS
  The impact of suppressed growth hormone (GH)/IGF-I levels on neoplastic initiation of PTEN-deficient prostate epithelia was assessed histologically and by epithelial-to-mesenchymal marker expression in Ghrhr D60G homozygous (lit/lit) and heterozygous (lit/+) pbARR2-Cre, PTEN(fl/fl) (PTEN-/-) mice. How suppressed GH/IGF-I levels impacted growth of PTEN-/- mouse-derived prostate cells (MPPK) was examined by growth and survival signaling of cells cultured in lit/+ or lit/lit serum.
  
  
  RESULTS
  Body weight, prostate weight and serum GH and IGF-I levels were reduced in lit/lit relative to lit/+ PTEN-/- littermates. While the anterior lobes of lit/+ PTEN-/- prostates consistently presented swollen, indicative of ductal blockage, the degree of prostatic dysplasia in 15- and 20-week-old lit/lit and lit/+ PTEN-/- mice was indistinguishable as measured by normalized prostatic weight, tissue histology, or probasin, PSP94, E-cadherin, N-cadherin and vimentin expression. However, growth and AKT activation of MPPK cells was decreased when cultured in lit/lit serum as compared with lit/+ serum and restored in lit/lit serum supplemented with IGF-I and, to a lesser extent, GH.
  
  
  CONCLUSIONS
  These results suggest that initiation of prostate carcinogenesis by loss of PTEN is not influenced by germline variation of genes encoding signaling molecules in the GH/IGF-I axis, but suggests that these factors may affect the progression of dysplastic phenotype and supports previous studies, indicating that the GH/IGF milieu does impact the growth of PTEN-deficient dysplastic prostatic cells once transformed.
authors.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Takahara
authors.forename: N
authors.initials: N
authors.lastname: Ibuki
authors.forename: M
authors.initials: M
authors.lastname: Ghaffari
authors.forename: H
authors.initials: H
authors.lastname: Tearle
authors.forename: C J
authors.initials: CJ
authors.lastname: Ong
authors.forename: H
authors.initials: H
authors.lastname: Azuma
authors.forename: M E
authors.initials: ME
authors.lastname: Gleave
authors.forename: M
authors.initials: M
authors.lastname: Pollak
authors.forename: M E
authors.initials: ME
authors.lastname: Cox
mesh_terms: D000727:Androgen-Binding Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019390:Arrestins / Q000235:genetics* / Q000378:metabolism*; D001835:Body Weight / Q000235:genetics; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D013006:Growth Hormone / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D029584:Prostatic Secretory Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D000071557:beta-Arrestins
chemical_list: D000727:Androgen-Binding Protein; D019390:Arrestins; D015820:Cadherins; D029584:Prostatic Secretory Proteins; D014746:Vimentin; D000071557:beta-Arrestins; C043076:beta-microseminoprotein; C027519:probasin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse