TY - JOUR
T1 - Pten dose dictates cancer progression in the prostate
AU - Trotman, Lloyd C.
AU - Niki, Masaru
AU - Dotan, Zohar A.
AU - Koutcher, Jason A.
AU - Di Cristofano, Antonio
AU - Xiao, Andrew
AU - Khoo, Alan S.
AU - Roy-Burman, Pradip
AU - Greenberg, Norman M.
AU - Van Dyke, Terry
AU - Cordon-Cardo, Carlos
AU - Pandolfi, Pier Paolo
PY - 2003
Y1 - 2003
N2 - Complete inactivation of the PTEN tumor suppressor gene is extremely common in advanced cancer, including prostate cancer (CaP). However, one PTEN allele is already lost in the vast majority of CaPs at presentation. To determine the consequence of PTEN dose variations on cancer progression, we have generated by homologous recombination a hypomorphic Pten mouse mutant series with decreasing Pten activity: Ptenhy/+ > Pten+/- > Pten hy/- (mutants in which we have rescued the embryonic lethality due to complete Pten inactivation) > Pten prostate conditional knockout (Pten pc) mutants. In addition, we have generated and comparatively analyzed two distinct Ptenpc mutants in which Pten is inactivated focally or throughout the entire prostatic epithelium. We find that the extent of Pten inactivation dictate in an exquisite dose-dependent fashion CaP progression, its incidence, latency, and biology. The dose of Pten affects key downstream targets such as Akt, p27Kip1, mTOR, and FOXO3. Our results provide conclusive genetic support for the notion that PTEN is haploinsufficient in tumor suppression and that its dose is a key determinant in cancer progression.
AB - Complete inactivation of the PTEN tumor suppressor gene is extremely common in advanced cancer, including prostate cancer (CaP). However, one PTEN allele is already lost in the vast majority of CaPs at presentation. To determine the consequence of PTEN dose variations on cancer progression, we have generated by homologous recombination a hypomorphic Pten mouse mutant series with decreasing Pten activity: Ptenhy/+ > Pten+/- > Pten hy/- (mutants in which we have rescued the embryonic lethality due to complete Pten inactivation) > Pten prostate conditional knockout (Pten pc) mutants. In addition, we have generated and comparatively analyzed two distinct Ptenpc mutants in which Pten is inactivated focally or throughout the entire prostatic epithelium. We find that the extent of Pten inactivation dictate in an exquisite dose-dependent fashion CaP progression, its incidence, latency, and biology. The dose of Pten affects key downstream targets such as Akt, p27Kip1, mTOR, and FOXO3. Our results provide conclusive genetic support for the notion that PTEN is haploinsufficient in tumor suppression and that its dose is a key determinant in cancer progression.
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U2 - 10.1371/journal.pbio.0000059
DO - 10.1371/journal.pbio.0000059
M3 - Article
C2 - 14691534
AN - SCOPUS:4243110417
SN - 1544-9173
VL - 1
JO - PLoS biology
JF - PLoS biology
IS - 3
ER -
