Naslov
An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice

Autori
Kinross, Kathryn M. ; Montgomery, Karen G. ; Kleinschmidt, Margarete ; Waring, Paul ; Ivetac, Ivan ; Tikoo, Anjali ; Saad, Mirette ; Hare, Lauren ; Roh, Vincent ; Mantamadiotis, Theo ; Sheppard, Karen E. ; Ryland, Georgina L. ; Campbell, Ian G. ; Gorringe, Kylie L. ; Christensen, James G. ; Cullinane, Carleen ; Hicks, Rodney J. ; Pearson, Richard B. ; Johnstone, Ricky W., McArthur, Grant A. ; Phillips, Wayne A.

Izvornik
The Journal of clinical investigation (0021-9738) 122 (2012), 2; 553-557

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
PI3K ; PIK3CA ; H1047R conditional mutant ; PTEN ; Akt ; mTOR ; cell signaling ; proliferation ; transformation ; tumorigenesis ; ovarian surface epithelium ; ovarian serous adenocarcinoma ; granulosa cell tumor.

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti, Biotehnologija u biomedicini (prirodno područje, biomedicina i zdravstvo, biotehničko područje)

POVEZANOST RADA