Abstract P2-07-04: Relevance of Mutated PIK3CA to Normal Mammary Gland Development and Malignancy
Authors: Merino VF , Park S , Liang X , Chun YS , Jones RJ , Sukumar S. 
Published: April 2011

Abstract
In the current study we generated transgenic mice with mammary gland specific-overexpression of PI3KCA wild type and mutant protein with the aim to characterize the effects of activation of PI3K signaling on normal mammary gland and tumor development. PIK3CA encodes p110α, the predominant isoform of the catalytic subunit of class 1A phosphatidylinositol 3-kinase (PI3K), a lipid phosphokinase. The family of PI3Ks provides signaling for diverse cellular functions, including proliferation, metabolism, migration, translation, apoptosis avoidance, and angiogenesis. Disruption of this tightly regulated pathway by gene loss (PTEN), mutation (PIK3CA, AKT1, or less commonly PIK3R1), or amplification (PIK3CA), is one of the most common alterations in human cancers. PIK3CA mutations result in constitutive activation of p110α , increasing lipid kinase activity and resulting in an increase in activated AKT. The majority of mutations in breast cancer occur at three hotspots: E542K and E545K at exon 9, which encodes the helical domain, and H1047R at exon 20, which encodes the kinase domain. Previously, it was described that human mammary epithelial cells expressing these alleles grew efficiently in soft agar and as orthotopic tumors in nude mice. In a mouse model in which PI3K is activated by forced recruitment of p110α to the membrane, increased ductal branching, alveolar hyperplasia, intraductal neoplasia and a low frequency of mammary tumors were observed. In breast carcinoma, mutations in PIK3CA and loss of PTEN function are almost always mutually exclusive. However, mutations in PIK3CA are often correlated with overexpression of Her2/neu (48%) in primary breast carcinomas, indicating that gain of function in these two signaling components could have a synergistic effect in counteracting PTEN. To date, no in vivo studies have been reported to determine if PIK3CA mutations play a causative role in breast tumorigenesis. In the current study we generated transgenic mice with mammary gland specific-overexpression of PIK3CA wild type and mutant protein and analyzed the effects of activation of PI3K signaling on normal mammary gland and tumor development. Mice harboring Exon 9 and Exon 20 mutations showed increased ductal branching at 8 weeks of age. Two mice harboring low and high copy numbers of Exon 20 mutation developed mammary tumors at 14 and 16 months of age, respectively. Histological analysis revealed that both were carcinomas with tubular, papillary and comedo features. PI3K activation increases the mammary epithelial stem cell population (CD24med/CD49f hi) in the normal gland. This population, which was characterized both by in vitro and in vivo assays, is highly expanded in the tumor cells. Tumor formation and mammary gland development is being observed in PIK3CA mutants crossed with MMTV-Her2neu mice. In conclusion, PI3K signaling activation appears to alter normal mammary gland development and initiate mammary tumor formation.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-07-04.