Progesterone promotes differentiation coupled to proliferation and pro-survival in the breast, but inhibits estrogen-driven growth in the reproductive tract and ovaries. Herein, it is demonstrated, using progesterone receptor (PR) isoform-specific ovarian cancer model systems, that PR-A and PR-B promote distinct gene expression profiles that differ from PR-driven genes in breast cancer cells. In ovarian cancer models, PR-A primarily regulates genes independently of progestin, while PR-B is the dominant ligand-dependent isoform. Notably, FOXO1 and the PR/FOXO1 target-gene p21 (CDKN1A) are repressed by PR-A, but induced by PR-B. In the presence of progestin, PR-B, but not PR-A, robustly induced cellular senescence via FOXO1-dependent induction of p21 and p15 (CDKN2B).
More...Progesterone promotes differentiation coupled to proliferation and pro-survival in the breast, but inhibits estrogen-driven growth in the reproductive tract and ovaries. Herein, it is demonstrated, using progesterone receptor (PR) isoform-specific ovarian cancer model systems, that PR-A and PR-B promote distinct gene expression profiles that differ from PR-driven genes in breast cancer cells. In ovarian cancer models, PR-A primarily regulates genes independently of progestin, while PR-B is the dominant ligand-dependent isoform. Notably, FOXO1 and the PR/FOXO1 target-gene p21 (CDKN1A) are repressed by PR-A, but induced by PR-B. In the presence of progestin, PR-B, but not PR-A, robustly induced cellular senescence via FOXO1-dependent induction of p21 and p15 (CDKN2B). Chromatin immunoprecipitation (ChIP) assays performed on PR-isoform specific cells demonstrated that while each isoform is recruited to the same PRE-containing region of the p21 promoter in response to progestin, only PR-B elicits active chromatin marks. Overexpression of constitutively active FOXO1 in PR-A-expressing cells conferred robust ligand-dependent upregulation of the PR-B target genes GZMA, IGFBP1, and p21, and induced cellular senescence. In the presence of endogenous active FOXO1, PR-A was phosphorylated on Ser294 and transactivated PR-B at PR-B target genes; these events were blocked by the FOXO1 inhibitor (AS1842856). PR isoform-specific regulation of the FOXO1/p21 axis recapitulated in human primary ovarian tumor explants treated with progestin; loss of progestin sensitivity correlated with high AKT activity.
IMPLICATIONS:
This study indicates FOXO1 as a critical component for progesterone signaling to promote cellular senescence and reveals a novel mechanism for transcription factor control of hormone sensitivity.
This SuperSeries is composed of the SubSeries listed below.
Overall design: Refer to individual Series
Less...| Accession | PRJNA285098; GEO: GSE69296 |
| Type | Umbrella project |
| Publications | Diep CH et al., "Active FOXO1 Is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming.", Mol Cancer Res, 2016 Feb;14(2):141-62 |
| Submission | Registration date: 27-May-2015
University of Minnesota |
| Relevance | Superseries |
Project Data:
| Resource Name | Number
of Links |
|---|
| Publications |
| PubMed | 1 |
| PMC | 1 |
| Other datasets |
| GEO DataSets | 3 |
GEO Data Details| Parameter | Value |
|---|
| Data volume, Spots | 1703628 |
| Data volume, Processed Mbytes | 42 |
| Data volume, Supplementary Mbytes | 42 |
Active FOXO1 is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming encompasses the following 2 sub-projects:
| Project Type | Number of Projects |
| Transcriptome or Gene expression | 2 |
BioProject
accession | Organism | Title |
|---|
| PRJNA285100 | Homo sapiens | Active FOXO1 is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming (University of Minnesota) | | PRJNA285101 | Homo sapiens | Active FOXO1 is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming (University of Minnesota) |
|