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
Molecular Cell | CELL PRESS | Published : 2020
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. ..View full abstract
Awarded by Victorian Cancer Agency Mid-Career Research Fellowship
Awarded by NHMRC New Investigator Grant
Awarded by National Breast Cancer Foundation Career Development Fellowship
The authors would like to thank members of the Mitchell lab for their feedback and Lee Wong for her kind support and insightful discussions. We thank the Monash Animal Research Platform for animal care and the Monash Bioinformatics Platform, in particular Stuart Archer and Nick Wong, for their support with data analysis. We would like to acknowledge Thierry Jarde and the Monash Organoid Program for technical assistance, the Monash Micro Imaging facility, Biochemistry Imaging Facility, Monash Histology Platform, Micromon Genomics, Monash FlowCore, and the Monash Health Translation Precinct Medical Genomics Facility. L.K.N. is supported by a Victorian Cancer Agency Mid-Career Research Fellowship (MCRF18026). This work was supported by a NHMRC New Investigator Grant (APP1100307) awarded to A.P. A.P. was supported by a National Breast Cancer Foundation Career Development Fellowship (ECF-16-002).