Projects per year
Abstract
The PTEN tumor suppressor controls cell death and survival by regulating functions of various molecular targets. While the role of PTEN lipid-phosphatase activity on PtdIns(3,4,5)P3 and inhibition of PI3K pathway is well characterized, the biological relevance of PTEN protein-phosphatase activity remains undefined. Here, using knockin (KI) mice harboring cancer-associated and functionally relevant missense mutations, we show that although loss of PTEN lipid-phosphatase function cooperates with oncogenic PI3K to promote rapid mammary tumorigenesis, the additional loss of PTEN protein-phosphatase activity triggered an extensive cell death response evident in early and advanced mammary tumors. Omics and drug-targeting studies revealed that PI3Ks act to reduce glucocorticoid receptor (GR) levels, which are rescued by loss of PTEN protein-phosphatase activity to restrain cell survival. Thus, we find that the dual regulation of GR by PI3K and PTEN functions as a rheostat that can be exploited for the treatment of PTEN loss-driven cancers.
Original language | English |
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Pages (from-to) | 279-295.e1-e8 |
Number of pages | 25 |
Journal | Molecular Cell |
Volume | 80 |
Issue number | 2 |
DOIs | |
Publication status | Published - 15 Oct 2020 |
Keywords
- failsafe mechanism
Projects
- 3 Finished
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Combating adaptive resistance to tageted therapy in triple-negative breast cancer
Nguyen, L., Swarbrick, A., Richardson, G., Loi, S. & Daly, R.
15/02/19 → 14/02/23
Project: Research
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Role of mutant PTEN in breast cancer development and metastasis
National Breast Cancer Foundation
1/01/16 → 31/12/19
Project: Research
Equipment
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Animal Research Platform (MARP)
Christine Findlay (Manager)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility
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Bioinformatics Platform
Deanna Deveson (Manager)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility
-
Biomedical Imaging (MBI)
Kylie Reid (Manager), Robert Brkljaca (Manager), Christoph Hagemeyer (Other) & David Wright (Other)
Office of the Vice-Provost (Research and Research Infrastructure)Facility/equipment: Facility