Active FOXO1 Is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming

Overview

Journal Mol Cancer Res

Specialty Cell Biology

Date 2015 Nov 19

PMID 26577046

Citations 21

Authors

Caroline H Diep

Todd P Knutson

Carol A Lange

Affiliations

Soon will be listed here.

Abstract

Unlabelled: Progesterone promotes differentiation coupled to proliferation and prosurvival 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.

Citing Articles

Progesterone Receptor Signaling Promotes Cancer Associated Fibroblast Mediated Tumorigenicity in ER+ Breast Cancer.

Diep C, Spartz A, Truong T, Dwyer A, El-Ashry D, Lange C Endocrinology. 2024; 165(9).

PMID: 39041201 PMC: 11492492. DOI: 10.1210/endocr/bqae092.

Hormone Receptors and Epithelial Ovarian Cancer: Recent Advances in Biology and Treatment Options.

Borella F, Fucina S, Mangherini L, Cosma S, Carosso A, Cusato J Biomedicines. 2023; 11(8).

PMID: 37626654 PMC: 10452581. DOI: 10.3390/biomedicines11082157.

Reevaluating the Role of Progesterone in Ovarian Cancer: Is Progesterone Always Protective?.

Mauro L, Spartz A, Austin J, Lange C Endocr Rev. 2023; 44(6):1029-1046.

PMID: 37261958 PMC: 11048595. DOI: 10.1210/endrev/bnad018.

Non-Coding RNAs Modulating Estrogen Signaling and Response to Endocrine Therapy in Breast Cancer.

Treeck O, Haerteis S, Ortmann O Cancers (Basel). 2023; 15(6).

PMID: 36980520 PMC: 10046587. DOI: 10.3390/cancers15061632.

Utilizing an Endogenous Progesterone Receptor Reporter Gene for Drug Screening and Mechanistic Study in Endometrial Cancer.

Li Y, Zhou W, Meng X, Murray S, Li L, Fronk A Cancers (Basel). 2022; 14(19).

PMID: 36230806 PMC: 9561963. DOI: 10.3390/cancers14194883.

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