Conditional activation of Pik3ca(H1047R) in a knock-in mouse model promotes mammary tumorigenesis and emergence of mutations.

Abstract

Oncogenic mutations in PIK3CA, which encodes the phosphoinositide-3-kinase (PI3K) catalytic subunit p110α, occur in ∼25% of human breast cancers. In this study, we report the development of a knock-in mouse model for breast cancer where the endogenous Pik3ca allele was modified to allow tissue-specific conditional expression of a frequently found Pik3ca(H1047R) (Pik3ca(e20H1047R)) mutant allele. We found that activation of the latent Pik3ca(H1047R) allele resulted in breast tumors with multiple histological types. Whole-exome analysis of the Pik3ca(H1047R)-driven mammary tumors identified multiple mutations, including Trp53 mutations that appeared spontaneously during the development of adenocarinoma and spindle cell tumors. Further, we used this model to test the efficacy of GDC-0941, a PI3K inhibitor, in clinical development, and showed that the tumors respond to PI3K inhibition.

• Authors: W Yuan, E Stawiski, V Janakiraman, E Chan, S Durinck, K A Edgar, N M Kljavin, C S Rivers, F Gnad, M Roose-Girma, P M Haverty, G Fedorowicz, S Heldens, R H Soriano, Z Zhang, J J Wallin, L Johnson, M Merchant, Z Modrusan, H M Stern, S Seshagiri
• Journal: Oncogene (Oncogene) Vol. 32 Issue 3 Pg. 318-26 (Jan 17 2013) ISSN: 1476-5594 [Electronic] England
• PMID: 22370636 (Publication Type: Journal Article)

Chemical References

• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Tumor Suppressor Protein p53
• Class I Phosphatidylinositol 3-Kinases
• Pik3ca protein, mouse

Topics

• Adenocarcinoma (genetics, pathology)
• Alleles
• Animals
• Base Sequence
• Class I Phosphatidylinositol 3-Kinases
• Enzyme Activation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knock-In Techniques
• Genomics
• Humans
• Mammary Neoplasms, Experimental (genetics, pathology)
• Mice
• Mutation
• Organ Specificity
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology)
• Tumor Suppressor Protein p53 (genetics)