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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 31993-32004 |
| Number of pages | 12 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 117 |
| Issue number | 50 |
| DOIs | |
| State | Published - Dec 15 2020 |
Keywords
- Antiprogestins
- BRCA
- Hormone
- Ovarian cancer
- Progesterone
ASJC Scopus subject areas
- General
Fingerprint
Dive into the research topics of 'Targeting progesterone signaling prevents metastatic ovarian cancer'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
Targeting progesterone signaling prevents metastatic ovarian cancer. / Kim, Olga; Park, Eun Young; Kwon, Sun Young et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, No. 50, 15.12.2020, p. 31993-32004.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Targeting progesterone signaling prevents metastatic ovarian cancer
AU - Kim, Olga
AU - Park, Eun Young
AU - Kwon, Sun Young
AU - Shin, Sojin
AU - Emerson, Robert E.
AU - Shin, Yong Hyun
AU - DeMayo, Francesco J.
AU - Lydon, John P.
AU - Coffey, Donna M.
AU - Hawkins, Shannon M.
AU - Quilliam, Lawrence A.
AU - Cheon, Dong Joo
AU - Fernández, Facundo M.
AU - Nephew, Kenneth P.
AU - Karpf, Adam R.
AU - Widschwendter, Martin
AU - Sood, Anil K.
AU - Bast, Robert C.
AU - Godwin, Andrew K.
AU - Miller, Kathy D.
AU - Cho, Chi Heum
AU - Kim, Jaeyeon
N1 - Funding Information: We are grateful to Dr. Martin M. Matzuk at Baylor College of Medicine for kindly sharing a mouse model of ovarian cancer and for his generous support of this work. We thank Solji Hyeon for her valuable technical contributions to this work. We also thank the Center for Genomics and Bioinformatics at Indiana University Bloomington for RNA sequencing and analysis; the Center for Research in Reproduction Ligand Assay and Analysis Core at the University of Virginia for hormone measurements; the Histology Core at Indiana University School of Medicine for tissue processing, sectioning, and hematoxylin/eosin; and Michele Park and Maura Kluthe of the Biospecimen Repository Core Facility at the University of Kansas Cancer Center for providing tissue sections, including BRCA1 RRSO specimens. We are also grateful to Antony Botros, Andro Botros, Anupama Ram, Samantha Guinn, Ebony Hargrove-Wiley, and Sylvia Yun for research assistance in mouse work. We also thank the following investigators for review of and helpful comments on the manuscript: Dr. Yang Yang-Hartwich at Yale University; Drs. Jeanne M. Schilder, Sharon E. Robertson, John J. Turchi, and Thomas D. Hurley at Indiana University School of Medicine; Dr. Carol Lange at the University of Minnesota; and Dr. Ronny Drapkin at the University of Pennsylvania Penn Ovarian Cancer Research Center. We thank Dr. Susan M. Domchek at the University of Pennsylvania Perelman School of Medicine, Dr. Louis Dubeau at the University of Southern California, and Dr. Kathleen Cho at the University of Michigan Medical School for reviewing the manuscript and providing valuable insights. This work is supported by the following grants or awards: R00CA179137 (J.K.) and R01CA218664 (F.M.F. and J.K.) from the US NIH National Cancer Institute (NCI); R01HD042311 (J.P.L.) from NIH National Institute of Child Health and Human Development; BCRF-19-109 (K.D.M. and J.K.) from Breast Cancer Research Foundation; P20 GM130423 (A.K.G.) from the National Institute of General Medical Sciences, and the University of Kansas Cancer Center's Cancer Center Support Grant (P30 CA168524); Frank Memorial Chair in Cancer in Cancer Research (A.K.S.); the MD Anderson Ovarian Specialized Program of Research Excellence from NCI (P50 CA217685) (R.C.B. and A.K.S.); the European Research Center Advanced Grant BRCA-ERC (742432) and the Eve Appeal (M.W.); a Vera Bradley Scholar award (O.K.); and Indiana University Health-Indiana University School of Medicine Strategic Research Initiative (J.K.). Also, we are grateful for generous support from the Vera Bradley Foundation for Breast Cancer Research. Funding Information: ACKNOWLEDGMENTS. We are grateful to Dr. Martin M. Matzuk at Baylor College of Medicine for kindly sharing a mouse model of ovarian cancer and for his generous support of this work. We thank Solji Hyeon for her valuable technical contributions to this work. We also thank the Center for Genomics and Bioinformatics at Indiana University Bloomington for RNA sequencing and analysis; the Center for Research in Reproduction Ligand Assay and Analysis Core at the University of Virginia for hormone measurements; the Histology Core at Indiana University School of Medicine for tissue processing, sectioning, and hematoxylin/eosin; and Michele Park and Maura Kluthe of the Biospecimen Repository Core Facility at the University of Kansas Cancer Center for providing tissue sections, including BRCA1 RRSO specimens. We are also grateful to Antony Botros, Andro Botros, Anupama Ram, Samantha Guinn, Ebony Hargrove-Wiley, and Sylvia Yun for research assistance in mouse work. We also thank the following investigators for review of and helpful comments on the manuscript: Dr. Yang Yang-Hartwich at Yale University; Drs. Jeanne M. Schilder, Sharon E. Robertson, John J. Turchi, and Thomas D. Hurley at Indiana University School of Medicine; Dr. Carol Lange at the University of Minnesota; and Dr. Ronny Drapkin at the University of Pennsylvania Penn Ovarian Cancer Research Center. We thank Dr. Susan M. Domchek at the University of Pennsylvania Perelman School of Medicine, Dr. Louis Dubeau at the University of Southern California, and Dr. Kathleen Cho at the University of Michigan Medical School for reviewing the manuscript and providing valuable insights. This work is supported by the following grants or awards: R00CA179137 (J.K.) and R01CA218664 (F.M.F. and J.K.) from the US NIH National Cancer Institute (NCI); R01HD042311 (J.P.L.) from NIH National Institute of Child Health and Human Development; BCRF-19-109 (K.D.M. and J.K.) from Breast Cancer Research Foundation; P20 GM130423 (A.K.G.) from the National Institute of General Medical Sciences, and the University of Kansas Cancer Center’s Cancer Center Support Grant (P30 CA168524); Frank Memorial Chair in Cancer in Cancer Research (A.K.S.); the MD Anderson Ovarian Specialized Program of Research Excellence from NCI (P50 CA217685) (R.C.B. and A.K.S.); the European Research Center Advanced Grant BRCA-ERC (742432) and the Eve Appeal (M.W.); a Vera Bradley Scholar award (O.K.); and Indiana University Health–Indiana University School of Medicine Strategic Research Initiative (J.K.). Also, we are grateful for generous support from the Vera Bradley Foundation for Breast Cancer Research. Publisher Copyright: © 2020 National Academy of Sciences. All rights reserved.
PY - 2020/12/15
Y1 - 2020/12/15
N2 - 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.
AB - 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.
KW - Antiprogestins
KW - BRCA
KW - Hormone
KW - Ovarian cancer
KW - Progesterone
UR - http://www.scopus.com/inward/record.url?scp=85098469877&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098469877&partnerID=8YFLogxK
U2 - 10.1073/pnas.2013595117
DO - 10.1073/pnas.2013595117
M3 - Article
C2 - 33262282
AN - SCOPUS:85098469877
VL - 117
SP - 31993
EP - 32004
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 50
ER -