A constitutively activated form of the p110beta isoform of PI3-kinase induces prostatic intraepithelial neoplasia in mice.
Recent work has shown that ablation of p110beta, but not p110alpha, markedly impairs tumorigenesis driven by loss of phosphatase and tensin homolog (PTEN) in the mouse prostate. Other laboratories have reported complementary data in human prostate tumor lines, suggesting that p110beta activation is necessary for tumorigenesis driven by PTEN loss. Given the multiple functions of PTEN, we wondered if p110beta activation also is sufficient for tumorigenesis. Here, we report that transgenic expression of a constitutively activated p110beta allele in the prostate drives prostate intraepithelial neoplasia formation. The resulting lesions are similar to, but are clearly distinct from, the ones arising from PTEN loss or Akt activation. Array analyses of transcription in multiple murine prostate tumor models featuring PI3K/AKT pathway activation allowed construction of a pathway signature that may be useful in predicting the prognosis of human prostate tumors.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Sang Hyun
SH
Lee
George
G
Poulogiannis
Saumyadipta
S
Pyne
Shidong
S
Jia
Lihua
L
Zou
Sabina
S
Signoretti
Massimo
M
Loda
Lewis Clayton
LC
Cantley
Thomas M
TM
Roberts
D000367:Age Factors; D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D016259:Genes, myc; D006801:Humans; D008297:Male; D008679:Metaplasia; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011467:Prostate / Q000201:enzymology; D019048:Prostatic Intraepithelial Neoplasia / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013045:Species Specificity
D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse