title: Physiological expression of the PI3K-activating mutation Pik3ca(H1047R) combines with Apc loss to promote development of invasive intestinal adenocarcinomas in mice.
abstract: PIK3CA, the gene encoding the p110α catalytic subunit of PI3K (phosphoinositide 3-kinase), is mutated in approximately 20% of sporadic CRCs (colorectal cancers), but the role of these mutations in the pathogenesis of CRC remains unclear. In the present study we used a novel mouse model to investigate the role of the Pik3caH1047R mutation, the most common PIK3CA mutation in CRC, during the development and progression of intestinal cancer. Our results demonstrate that Pik3caH1047R, when expressed at physiological levels, is insufficient to initiate intestinal tumorigenesis; however, in the context of Apc (adenomatous polyposis coli) loss, which is observed in 80% of CRCs and by itself results in benign intestinal adenomas, the Pik3caH1047R mutation promotes the development of highly aggressive and invasive adenocarcinomas in both the small and large intestines. The results of the present study show that an activating Pik3ca mutation can act in tandem with Apc loss to drive the progression of gastrointestinal cancer and thus this disease may be susceptible to therapeutic targeting using PI3K pathway inhibitors.
authors: Lauren M
authors: LM
authors: Hare
authors: Toby J
authors: TJ
authors: Phesse
authors: ¶Department of Pathology, University of Melbourne, Parkville, VIC, Australia.
authors: Paul M
authors: PM
authors: Waring
authors: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors: Karen G
authors: KG
authors: Montgomery
authors: Kathryn M
authors: KM
authors: Kinross
authors: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors: Kevin
authors: K
authors: Mills
authors: *Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors: Vincent
authors: V
authors: Roh
authors: Joan K
authors: JK
authors: Heath
authors: Robert G
authors: RG
authors: Ramsay
authors: Matthias
authors: M
authors: Ernst
authors: Wayne A
authors: WA
authors: Phillips
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055879:Gene Knock-In Techniques; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; C546639:Pik3ca protein, mouse