Progesterone Receptors Promote Quiescence and Ovarian Cancer Cell Phenotypes via DREAM in p53-Mutant Fallopian Tube Models-Reference-Cited by-同舟云学术

Progesterone Receptors Promote Quiescence and Ovarian Cancer Cell Phenotypes via DREAM in p53-Mutant Fallopian Tube Models

Published:2021-03-23 Issue:7 Volume:106 Page:1929-1955
ISSN:0021-972X
Container-title:The Journal of Clinical Endocrinology & Metabolism
language:en
Short-container-title:

Author:

Mauro Laura J¹²^ORCID,Seibel Megan I¹,Diep Caroline H¹,Spartz Angela¹,Perez Kerkvliet Carlos¹,Singhal Hari³,Swisher Elizabeth M⁴,Schwartz Lauren E⁵,Drapkin Ronny⁶,Saini Siddharth⁷,Sesay Fatmata⁷,Litovchick Larisa⁷,Lange Carol A¹⁸^ORCID

Affiliation:

1. University of Minnesota, Masonic Cancer Center, Minneapolis, MN 55455, USA

2. University of Minnesota, Department of Animal Science, St. Paul, MN 55108, USA

3. Northwestern University, Department of Surgery, Feinberg School of Medicine, Chicago, IL 60611, USA

4. University of Washington Seattle, Dept Obstetrics & Gynecology, Division of Gynecologic Oncology, Seattle, WA 98109, USA

5. University of Pennsylvania, Dept of Pathology and Laboratory Medicine, Philadelphia, PA 19104, USA

6. University of Pennsylvania, Penn Ovarian Cancer Research Center, Dept Obstetrics & Gynecology, Philadelphia, PA 19104, USA

7. Virginia Commonwealth University, Massey Cancer Center, Dept. Internal Medicine, Division of Hematology, Oncology & Palliative Care, Richmond, VA 23298, USA

8. University of Minnesota, Dept Medicine, Division of Hematology, Oncology & Transplantation, Minneapolis, MN 55455, USA

Abstract

Abstract Context The ability of ovarian steroids to modify ovarian cancer (OC) risk remains controversial. Progesterone is considered to be protective; recent studies indicate no effect or enhanced OC risk. Knowledge of progesterone receptor (PR) signaling during altered physiology that typifies OC development is limited. Objective This study defines PR-driven oncogenic signaling mechanisms in p53-mutant human fallopian tube epithelia (hFTE), a precursor of the most aggressive OC subtype. Methods PR expression in clinical samples of serous tubal intraepithelial carcinoma (STIC) lesions and high-grade serous OC (HGSC) tumors was analyzed. Novel PR-A and PR-B isoform-expressing hFTE models were characterized for gene expression and cell cycle progression, emboli formation, and invasion. PR regulation of the DREAM quiescence complex and DYRK1 kinases was established. Results STICs and HGSC express abundant activated phospho-PR. Progestin promoted reversible hFTE cell cycle arrest, spheroid formation, and invasion. RNAseq/biochemical studies revealed potent ligand-independent/-dependent PR actions, progestin-induced regulation of the DREAM quiescence complex, and cell cycle target genes through enhanced complex formation and chromatin recruitment. Disruption of DREAM/DYRK1s by pharmacological inhibition, HPV E6/E7 expression, or DYRK1A/B depletion blocked progestin-induced cell arrest and attenuated PR-driven gene expression and associated OC phenotypes. Conclusion Activated PRs support quiescence and pro-survival/pro-dissemination cell behaviors that may contribute to early HGSC progression. Our data support an alternative perspective on the tenet that progesterone always confers protection against OC. STICs can reside undetected for decades prior to invasive disease; our studies reveal clinical opportunities to prevent the ultimate development of HGSC by targeting PRs, DREAM, and/or DYRKs.

Funder

Minnesota Ovarian Cancer Alliance

University of Minnesota

National Institutes of Health

National Cancer Institute

Dr. Miriam and Sheldon G. Adelson Medical Research Foundation

Claneil Foundation

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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