An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice.
Mutations in the gene encoding the p110α subunit of PI3K (PIK3CA) that result in enhanced PI3K activity are frequently observed in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis, we generated mice in which a PIK3CA mutation commonly detected in human cancers (the H1047R mutation) could be conditionally knocked into the endogenous Pik3ca locus. Activation of this mutation in the mouse ovary revealed that alone, Pik3caH1047R induced premalignant hyperplasia of the ovarian surface epithelium but no tumors. Concomitantly, we analyzed several human ovarian cancers and found PIK3CA mutations coexistent with KRAS and/or PTEN mutations, raising the possibility that a secondary defect in a co-regulator of PI3K activity may be required for mutant PIK3CA to promote transformation. Consistent with this notion, we found that Pik3caH1047R mutation plus Pten deletion in the mouse ovary led to the development of ovarian serous adenocarcinomas and granulosa cell tumors. Both mutational events were required for early, robust Akt activation. Pharmacological inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. These results demonstrate that the Pik3caH1047R mutation with loss of Pten is enough to promote ovarian cell transformation and that we have developed a model system for studying possible therapies.
Cancer Research Division, Peter MacCallum Cancer Centre (Peter Mac), East Melbourne, Victoria, Australia.
Kathryn M
KM
Kinross
Karen G
KG
Montgomery
Margarete
M
Kleinschmidt
Paul
P
Waring
Ivan
I
Ivetac
Anjali
A
Tikoo
Mirette
M
Saad
Lauren
L
Hare
Vincent
V
Roh
Theo
T
Mantamadiotis
Karen E
KE
Sheppard
Georgina L
GL
Ryland
Ian G
IG
Campbell
Kylie L
KL
Gorringe
James G
JG
Christensen
Carleen
C
Cullinane
Rodney J
RJ
Hicks
Richard B
RB
Pearson
Ricky W
RW
Johnstone
Grant A
GA
McArthur
Wayne A
WA
Phillips
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010053:Ovary / Q000033:anatomy & histology / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D015996:Survival Rate
D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C546639:Pik3ca protein, mouse; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse