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

• Published in: Molecular cell 2020-10, Vol.80 (2), p.279-295.e8
• Main Authors: Yip, Hon Yan K., Chee, Annabel, Ang, Ching-Seng, Shin, Sung-Young, Ooms, Lisa M., Mohammadi, Zainab, Phillips, Wayne A., Daly, Roger J., Cole, Timothy J., Bronson, Roderick T., Nguyen, Lan K., Tiganis, Tony, Hobbs, Robin M., McLean, Catriona A., Mitchell, Christina A., Papa, Antonella
• Format: Article
• Language: English
• Subjects: failsafe mechanism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2020.09.027

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. [Display omitted] •Loss of PTEN function cooperates with oncogenic PIK3CA in mammary tumorigenesis•Targeted AKT inhibition suppresses growth of PTEN and PI3K mutant mammary organoids•Loss of PTEN protein-phosphatase activity sensitizes tumors and cells to death•GR mediates the failsafe mechanism driven by loss of PTEN protein function Yip et al. demonstrate that loss of the tumor suppressor PTEN synergizes with mutant PI3K in mammary tumorigenesis but also renders tumor cells sensitive to death induced by the glucocorticoid receptor (GR). The authors conclude that GR action and AKT inhibition can provide a new treatment for PTEN/PI3K mutant cancers.