Targeting progesterone signaling prevents metastatic ovarian cancer

Proc Natl Acad Sci U S A. 2020 Dec 15;117(50):31993-32004. doi: 10.1073/pnas.2013595117. Epub 2020 Dec 1.

Abstract

Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene.

Keywords: BRCA; antiprogestins; hormone; ovarian cancer; progesterone.

Publication types

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

MeSH terms

  • Adult
  • Animals
  • BRCA1 Protein / genetics*
  • Breast / pathology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Breast Neoplasms / prevention & control
  • Cystadenocarcinoma, Serous / chemistry
  • Cystadenocarcinoma, Serous / genetics
  • Cystadenocarcinoma, Serous / pathology
  • Cystadenocarcinoma, Serous / prevention & control*
  • Disease Models, Animal
  • Estradiol / administration & dosage
  • Female
  • Humans
  • Mice
  • Middle Aged
  • Mifepristone / pharmacology*
  • Mifepristone / therapeutic use
  • Mutation
  • Neoplasms, Experimental / chemically induced
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / prevention & control
  • Ovarian Neoplasms / chemically induced
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / prevention & control*
  • Ovary / pathology
  • Ovary / surgery
  • Progesterone / administration & dosage
  • Progesterone / antagonists & inhibitors*
  • Progesterone / metabolism
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism
  • Salpingo-oophorectomy
  • Signal Transduction / drug effects
  • Signal Transduction / genetics

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Receptors, Progesterone
  • Mifepristone
  • Progesterone
  • Estradiol