Title | The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. |
Publication Type | Journal Article |
Year of Publication | 2005 |
Authors | Zhao JJ, Liu Z, Wang L, Shin E, Loda MF, Roberts TM |
Journal | Proc Natl Acad Sci U S A |
Volume | 102 |
Issue | 51 |
Pagination | 18443-8 |
Date Published | 2005 Dec 20 |
ISSN | 0027-8424 |
Keywords | Alleles, Animals, Antigens, Polyomavirus Transforming, Binding Sites, Biomarkers, Tumor, Cell Line, Cell Transformation, Neoplastic, Class I Phosphatidylinositol 3-Kinases, Epithelial Cells, Humans, Mammary Glands, Human, Mice, Mice, Nude, Molecular Weight, Mutation, Myristic Acid, Neoplasm Transplantation, Neoplasms, Phosphatidylinositol 3-Kinases, Tumor Suppressor Protein p53 |
Abstract | The PIK3CA gene encoding the p110alpha subunit of Class IA phosphatidylinositol 3-kinases (PI3Ks) is frequently mutated in human tumors. Mutations in the PIK3CB gene encoding p110beta, the only other widely expressed Class IA PI3K, have not been reported. We compared the biochemical activity and transforming potential of mutant forms of p110alpha and p110beta in a human mammary epithelial cell system. The two most common tumor-derived alleles of p110alpha, H1047R and E545K, potently activated PI3K signaling. Human mammary epithelial cells expressing these alleles grew efficiently in soft agar and as orthotopic tumors in nude mice. We also examined a third class of mutations in p110alpha, those in the p85-binding domain. A representative tumor-derived p85-binding-domain mutant R38H showed modestly reduced p85 binding and weakly activated PI3K/Akt signaling. In contrast, a deletion mutant lacking the entire p85-binding domain efficiently activated PI3K signaling. When we constructed in p110beta a mutation homologous to the E545K allele of p110alpha, the resulting p110beta mutant was only weakly activated and allowed minimal soft-agar growth. However, a gene fusion of p110beta with the membrane anchor from c-Src was highly active and transforming in both soft-agar and orthotopic nude mouse assays. Thus, although introduction of activating mutations from p110alpha at the corresponding sites in p110beta failed to render the enzyme oncogenic in human cells, the possibility remains that other mutations might activate the beta isoform. |
DOI | 10.1073/pnas.0508988102 |
Alternate Journal | Proc Natl Acad Sci U S A |
PubMed ID | 16339315 |
PubMed Central ID | PMC1317954 |
Grant List | P50 CA090381 / CA / NCI NIH HHS / United States P01-CA50661 / CA / NCI NIH HHS / United States CA30002 / CA / NCI NIH HHS / United States R37 CA030002 / CA / NCI NIH HHS / United States CA089021 / CA / NCI NIH HHS / United States 5P50CA090381-05 / CA / NCI NIH HHS / United States R01 CA030002 / CA / NCI NIH HHS / United States P01 CA089021 / CA / NCI NIH HHS / United States P01 CA050661 / CA / NCI NIH HHS / United States |
Related Faculty:
Massimo Loda, M.D.