PI3K-p110α mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K-p85α
| Autor: | Carolynn E. Ohlson, Jennifer M. Spangle, Lauren M. Thorpe, Lewis C. Cantley, Thomas M. Roberts, Hailing Cheng, Jean J. Zhao |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Genotype Class I Phosphatidylinositol 3-Kinases medicine.medical_treatment Breast Neoplasms P110α Biology Bioinformatics medicine.disease_cause Gene Expression Regulation Enzymologic Targeted therapy Mice 03 medical and health sciences Mammary Glands Animal 0302 clinical medicine Breast cancer PIK3R1 Cell Line Tumor medicine Animals Humans PI3K/AKT/mTOR pathway Cell Proliferation Oligonucleotide Array Sequence Analysis Gene knockdown Mutation Multidisciplinary Cancer Epithelial Cells Biological Sciences medicine.disease Class Ia Phosphatidylinositol 3-Kinase Enzyme Activation Gene Expression Regulation Neoplastic Cell Transformation Neoplastic 030104 developmental biology Gene Knockdown Techniques 030220 oncology & carcinogenesis Cancer research Intercellular Signaling Peptides and Proteins Female Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 114:7095-7100 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1704706114 |
| Popis: | Mutation or loss of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is emerging as a transforming factor in cancer, but the mechanism of transformation has been controversial. Here we find that hemizygous deletion of the PIK3R1 gene encoding p85α is a frequent event in breast cancer, with PIK3R1 expression significantly reduced in breast tumors. PIK3R1 knockdown transforms human mammary epithelial cells, and genetic ablation of Pik3r1 accelerates a mouse model of HER2/neu-driven breast cancer. We demonstrate that partial loss of p85α increases the amount of p110α-p85 heterodimers bound to active receptors, augmenting PI3K signaling and oncogenic transformation. Pan-PI3K and p110α-selective pharmacological inhibition effectively blocks transformation driven by partial p85α loss both in vitro and in vivo. Together, our data suggest that p85α plays a tumor-suppressive role in transformation, and suggest that p110α-selective therapeutics may be effective in the treatment of breast cancer patients with PIK3R1 loss. |
| Databáze: | OpenAIRE |
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