Luminal Expression of PIK3CA Mutant H1047R in the Mammary Gland Induces Heterogeneous Tumors

Abstract

The phosphoinositide 3-kinase (PI3K) signaling cascade, a key mediator of cellular survival, growth, and metabolism, is frequently altered in human cancer. Activating mutations in PIK3CA, which encodes the a-catalytic subunit of PI3K, occur in approximately 30% of breast cancers. These mutations result in constitutive activity of the enzyme and are oncogenic, but it is not known whether they are sufficient to induce mammary carcinomas in mice. In the present study, we show that the expression of mutant PIK3CA H1047R in the luminal mammary epithelium evokes heterogeneous tumors that express luminal and basal markers and are positive for the estrogen receptor. Our results suggest that the PIK3CA H1047R oncogene targets a multipotent progenitor cell and, furthermore, show that this model recapitulates features of human breast tumors with PIK3CA H1047R. Cancer Res; 71(13); 4344-51. Ó2011 AACR.

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

“…In 2 mice, we observed microinvasion of the ovarian stroma, indicating that the epithelial proliferation was neoplastic despite the absence of definitive cytological evidence of malignancy. The inability of Pik3ca H1047R to induce ovarian tumorigenesis differs from transgenic mouse models of Pik3ca H1047R inducing lung and breast (20)(21)(22)(23) tumors, but these models are driven by overexpressed Pik3ca H1047R rather than mutation of the endogenous gene, as occurs in human tumors. Possibly, the ovary could be less susceptible to transformation via a single mutation compared with other tissue types.…”

Correlation of DLC1 gene methylation with oncogenic PIK3CA mutations in extramammary Paget's disease

“…27 These mutations are known to result in elevated catalytic activity, which leads to oncogenic transformation. 39 However, in our study, the Glu545Ala (c. 1634A4C) mutation in exon 9 of PIK3CA showed a high frequency in PIK3CA mutation-positive extramammary Paget's disease cases (20 of 32), as compared with only 5 cases with the Glu542Lys, 1 case with Glu545Lys, 2 cases with His1047Tyr, and 8 cases with His1047Arg.…”

“…[23][24][25][26] More than 80% of these mutations are clustered in exon 9, which encodes the protein's helical domain, and in exon 20, which encodes the kinase domain. 27 However, correlation analysis of the PIK3CA genetic alterations to determine their clinicopathological significance for extramammary Paget's disease has not yet been reported in the literature.…”

Disruption of epithelial architecture caused by loss of PTEN or by oncogenic mutant p110α/PIK3CA but not by HER2 or mutant AKT1

“…Around a third of breast cancers display a mutation or deletion of at least one copy of the PTEN gene, 25% have an activating mutation in PIK3CA, which encodes the p110 component of PI3K and around 5% have an activating mutation in AKT1 [4][5][6][7][8]. The causal role of these PI3K pathway mutations in breast cancer has been supported by the rapid development of mammary tumours in mice either lacking Pten or expressing an active mutant PIK3CA H1047R selectively in the breast [9][10][11]. Additionally, the identification of PIK3CA mutations in early stage tumours suggests that their selection may be an early event in mammary tumorigenesis [12] but the co-existence of multiple genetic changes in different PI3K pathway components implies that these changes may be selected independently [3].…”