E-Poster Presentation 33rd Lorne Cancer Conference 2021

Control of Glucocorticoid Receptor Levels by PTEN Establishes a Failsafe Mechanism for Tumor Suppression   (#140)

Kelvin Yip 1 , Annabel Chee 1 , Ching-Seng Ang 2 , Sung- Young Shin 1 , Lisa Cole 1 , Zainab Mohammadi 1 , Wayne Phillps 1 2 3 4 , Roger J Daly 1 , Timothy J Cole 1 , Roderick Bronson 5 , Lan K Nguyen 1 , Tony Tiganis 1 3 , Robin Hobbs 5 6 , Catriona McLean 5 , Christina Mitchell 1 , Antonella Papa 1
  1. Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia
  2. Bio21 Mass Spectrometry and Proteomics Facility, The University of Melbourne, Parkville, VIC 3010, Australia
  3. Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
  4. The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
  5. Department of Anatomical Pathology, Alfred Hospital, Prahran, VIC 3181, Australia
  6. Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia

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.