Loss of PTEN is associated with progression to androgen independence.
BACKGROUND
Progression to a lethal androgen-independent (AI) stage of advanced prostate cancer is a critical clinical obstacle limiting patient survival. PTEN inactivation is frequently observed in advanced prostate cancer and correlates with a poor prognosis. However, the functional significance of PTEN inactivation in AI progression has not been demonstrated.


METHODS
PTEN expression was examined in benign, hormone naïve and AI human prostate cancer specimens, and in recurrent AI Shionogi tumors. The effect of antisense oligonucleotide (ASO)-mediated PTEN downregulation in AI progression of the Shionogi tumor model was determined.


RESULTS
Significantly reduced PTEN expression was observed in AI versus benign and hormone naïve prostate tumors. Seven of 14 AI Shionogi tumors exhibited marked downregulation or complete loss of PTEN. ASO-mediated PTEN inhibition reduced androgen-withdrawal induced regression of Shionogi tumors and accelerated AI progression.


CONCLUSIONS
These data suggest that PTEN inactivation may play a role in progression to androgen independence.
The Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
Jerod
J
Bertram
James W
JW
Peacock
Ladan
L
Fazli
Alice L-F
AL
Mui
Stephen W
SW
Chung
Michael E
ME
Cox
Brett
B
Monia
Martin E
ME
Gleave
Christopher J
CJ
Ong
D000728:Androgens / Q000032:analysis / Q000502:physiology*; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D018450:Disease Progression; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016153:Genes, Suppressor / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009367:Neoplasm Staging; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology
D000728:Androgens; D016376:Oligonucleotides, Antisense; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human