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

J Clin Endocrinol Metab. 2021 Jun 16;106(7):1929-1955. doi: 10.1210/clinem/dgab195.

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.

Keywords: DREAM; DYRK1 kinases; STIC; fallopian tube epithelia; ovarian cancer; progesterone.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis / genetics
  • Cell Growth Processes / genetics*
  • Cell Line, Tumor
  • Cystadenocarcinoma, Serous / genetics*
  • Fallopian Tube Neoplasms / genetics*
  • Fallopian Tubes / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Kv Channel-Interacting Proteins / metabolism*
  • Ovarian Neoplasms / genetics
  • Phenotype
  • Receptors, Progesterone / metabolism*
  • Repressor Proteins / metabolism*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • KCNIP3 protein, human
  • Kv Channel-Interacting Proteins
  • Receptors, Progesterone
  • Repressor Proteins
  • Tumor Suppressor Protein p53