Control of Glucocorticoid Receptor Levels by PTEN Establishes a Failsafe Mechanism for Tumor Suppression

Hon Yan K. Yip, Annabel Chee, Ching Seng Ang, Sung Young Shin, Lisa M. Ooms, Zainab Mohammadi, Wayne A. Phillips, Roger J. Daly, Timothy J. Cole, Roderick T. Bronson, Lan K. Nguyen, Tony Tiganis, Robin M. Hobbs, Catriona A. McLean, Christina A. Mitchell, Antonella Papa

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 languageEnglish
Pages (from-to)279-295.e8
JournalMolecular Cell
Volume80
Issue number2
DOIs
StatePublished - 15 Oct 2020
Externally publishedYes

Keywords

  • failsafe mechanism

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