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

Abstract

Highlights d Loss of PTEN function cooperates with oncogenic PIK3CA in mammary tumorigenesis d Targeted AKT inhibition suppresses growth of PTEN and PI3K mutant mammary organoids d Loss of PTEN protein-phosphatase activity sensitizes tumors and cells to death d GR mediates the failsafe mechanism driven by loss of PTEN protein function

Generation and functional characterization of murine mammary organoids

“… Alternative for tumor-derived cells: The experimental steps described in this protocol can also be used to isolate and establish 3D-cultures of tumor epithelial cells (tumoroids) derived from mammary tumors ( Figure 6 ) ( Duarte et al., 2018 ). In our experimental settings, we have successfully generated mammary tumoroids from tumors driven by cancer mutations in the tumor suppressor PTEN and the proto-oncogene PI3K ( Yip et al., 2020 ). For tumor samples: Process mice as in Step 2.…”

“…These detailed protocols also include procedures to perform assays that can be adopted to screen response to drug treatments and to inform better therapies. For details on potential applications and use of this protocol, please refer to Yip et al. (2020) .…”

PTEN and Other PtdIns(3,4,5)P3 Lipid Phosphatases in Breast Cancer

“…Rather, on a Pik3ca-mutant background, Pten C124S/+ mutation sensitized tumour epithelial cells and mammary organoids to cell death induced by the glucocorticoid receptor (GR) [64]. These findings demonstrate that under suboptimal and stressful growing conditions, loss of PTEN protein function triggers a failsafe mechanism in a cell-autonomous manner, that can be exploited in combination therapies with AKT inhibitors for breast cancer treatment [64].…”

“…However, the generation of Pten knock-in mice harbouring the Pten G129E mutation, with loss of PTEN lipid phosphatase function only, and the Pten C124S mutation, with loss of PTEN lipid and protein phosphatase activity, has shown that PTEN regulation of PtdIns(3,4,5)P 3 levels is the only essential PTEN function during embryonic development and in tumour initiation [42]. In addition, loss of PTEN lipid phosphatase function (Pten G129E/+ ) in mice with the Pik3ca H1047R mutation, promoted rapid development of advanced-stage and invasive mammary tumours, but the additional loss of PTEN protein phosphatase activity did not further exacerbate the phenotype [64]. Rather, on a Pik3ca-mutant background, Pten C124S/+ mutation sensitized tumour epithelial cells and mammary organoids to cell death induced by the glucocorticoid receptor (GR) [64].…”

“…In addition, loss of PTEN lipid phosphatase function (Pten G129E/+ ) in mice with the Pik3ca H1047R mutation, promoted rapid development of advanced-stage and invasive mammary tumours, but the additional loss of PTEN protein phosphatase activity did not further exacerbate the phenotype [64]. Rather, on a Pik3ca-mutant background, Pten C124S/+ mutation sensitized tumour epithelial cells and mammary organoids to cell death induced by the glucocorticoid receptor (GR) [64]. These findings demonstrate that under suboptimal and stressful growing conditions, loss of PTEN protein function triggers a failsafe mechanism in a cell-autonomous manner, that can be exploited in combination therapies with AKT inhibitors for breast cancer treatment [64].…”