Targeting progesterone signaling prevents metastatic ovarian cancer.
Adult
Animals
BRCA1 Protein
/ genetics
Breast
/ pathology
Breast Neoplasms
/ genetics
Cystadenocarcinoma, Serous
/ chemistry
Disease Models, Animal
Estradiol
/ administration & dosage
Female
Humans
Mice
Middle Aged
Mifepristone
/ pharmacology
Mutation
Neoplasms, Experimental
/ chemically induced
Ovarian Neoplasms
/ chemically induced
Ovary
/ pathology
Progesterone
/ administration & dosage
Receptors, Progesterone
/ genetics
Salpingo-oophorectomy
Signal Transduction
/ drug effects
BRCA
antiprogestins
hormone
ovarian cancer
progesterone
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
15 12 2020
15 12 2020
Historique:
pubmed:
3
12
2020
medline:
2
2
2021
entrez:
2
12
2020
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 33262282
pii: 2013595117
doi: 10.1073/pnas.2013595117
pmc: PMC7749341
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
Receptors, Progesterone
0
Mifepristone
320T6RNW1F
Progesterone
4G7DS2Q64Y
Estradiol
4TI98Z838E
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
31993-32004Subventions
Organisme : NCI NIH HHS
ID : P50 CA217685
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA168524
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM130423
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA179137
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD042311
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA218664
Pays : United States
Déclaration de conflit d'intérêts
Competing interest statement: J.K. and K.D.M. are listed as inventors on patent applications filed by Indiana University related to targeting progesterone signaling.
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