Targeting progesterone signaling prevents metastatic ovarian cancer

Olga Kim; Eun Young Park; Sun Young Kwon; Sojin Shin; Robert E Emerson; Yong-Hyun Shin; Francesco J DeMayo; John P Lydon; Donna M Coffey; Shannon M Hawkins; Lawrence A Quilliam; Dong-Joo Cheon; Facundo M Fernández; Kenneth P Nephew; Adam R Karpf; Martin Widschwendter; Anil K Sood; Robert C Bast Jr; Andrew K Godwin; Kathy D Miller; Chi-Heum Cho; Jaeyeon Kim

doi:10.1073/pnas.2013595117

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.

Authors

Olga Kim¹, Eun Young Park¹, Sun Young Kwon², Sojin Shin³, Robert E Emerson⁴, Yong-Hyun Shin¹, Francesco J DeMayo⁵, John P Lydon⁶, Donna M Coffey⁷, Shannon M Hawkins⁸, Lawrence A Quilliam¹, Dong-Joo Cheon⁹, Facundo M Fernández¹⁰, Kenneth P Nephew¹¹, Adam R Karpf¹², Martin Widschwendter^{13

14

15}, Anil K Sood^{16

17}, Robert C Bast Jr¹⁸, Andrew K Godwin¹⁹, Kathy D Miller²⁰, Chi-Heum Cho²¹, Jaeyeon Kim²²

Affiliations

¹ Department of Biochemistry and Molecular Biology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202.
² Department of Pathology, School of Medicine, Keimyung University, 41931 Daegu, Republic of Korea.
³ Department of Obstetrics and Gynecology, School of Medicine, Keimyung University, 41931 Daegu, Republic of Korea.
⁴ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202.
⁵ Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
⁶ Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX 77030.
⁷ Department of Pathology and Genomic Medicine, Houston Methodist and Weill Cornell Medical College, Houston, TX 77030.
⁸ Department of Obstetrics and Gynecology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202.
⁹ Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208.
¹⁰ School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332.
¹¹ Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405.
¹² Eppley Institute for Cancer Research, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198.
¹³ Department of Women's Cancer, Institute for Women's Health, University College London, WC1E 6AU London, United Kingdom.
¹⁴ Research Institute for Biomedical Aging Research, Universität Innsbruck, 6020 Innsbruck, Austria.
¹⁵ European Translational Oncology Prevention and Screening (EUTOPS) Institute, Universität Innsbruck, 6060 Hall in Tirol, Austria.
¹⁶ Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
¹⁷ Department of Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
¹⁸ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
¹⁹ Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160.
²⁰ Department of Medicine, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202 [email protected] [email protected] [email protected].
²¹ Department of Obstetrics and Gynecology, School of Medicine, Keimyung University, 41931 Daegu, Republic of Korea; [email protected] [email protected] [email protected].
²² Department of Biochemistry and Molecular Biology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202; [email protected] [email protected] [email protected].

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding