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Research Article

Targeting progesterone signaling prevents metastatic ovarian cancer

View ORCID ProfileOlga Kim, View ORCID ProfileEun Young Park, View ORCID ProfileSun Young Kwon, Sojin Shin, View ORCID ProfileRobert E. Emerson, Yong-Hyun Shin, View ORCID ProfileFrancesco J. DeMayo, View ORCID ProfileJohn P. Lydon, Donna M. Coffey, View ORCID ProfileShannon M. Hawkins, Lawrence A. Quilliam, View ORCID ProfileDong-Joo Cheon, Facundo M. Fernández, Kenneth P. Nephew, View ORCID ProfileAdam R. Karpf, View ORCID ProfileMartin Widschwendter, Anil K. Sood, View ORCID ProfileRobert C. Bast Jr, View ORCID ProfileAndrew K. Godwin, Kathy D. Miller, Chi-Heum Cho, and View ORCID ProfileJaeyeon Kim
PNAS December 15, 2020 117 (50) 31993-32004; first published December 1, 2020; https://doi.org/10.1073/pnas.2013595117
Olga Kim
aDepartment of Biochemistry and Molecular Biology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202;
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  • ORCID record for Olga Kim
Eun Young Park
aDepartment of Biochemistry and Molecular Biology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202;
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  • ORCID record for Eun Young Park
Sun Young Kwon
bDepartment of Pathology, School of Medicine, Keimyung University, 41931 Daegu, Republic of Korea;
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  • ORCID record for Sun Young Kwon
Sojin Shin
cDepartment of Obstetrics and Gynecology, School of Medicine, Keimyung University, 41931 Daegu, Republic of Korea;
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Robert E. Emerson
dDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202;
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  • ORCID record for Robert E. Emerson
Yong-Hyun Shin
aDepartment of Biochemistry and Molecular Biology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202;
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Francesco J. DeMayo
eReproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709;
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  • ORCID record for Francesco J. DeMayo
John P. Lydon
fDepartment of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX 77030;
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  • ORCID record for John P. Lydon
Donna M. Coffey
gDepartment of Pathology and Genomic Medicine, Houston Methodist and Weill Cornell Medical College, Houston, TX 77030;
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Shannon M. Hawkins
hDepartment of Obstetrics and Gynecology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202;
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  • ORCID record for Shannon M. Hawkins
Lawrence A. Quilliam
aDepartment of Biochemistry and Molecular Biology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202;
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Dong-Joo Cheon
iDepartment of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208;
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Facundo M. Fernández
jSchool of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332;
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Kenneth P. Nephew
kMedical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405;
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Adam R. Karpf
lEppley Institute for Cancer Research, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198;
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  • ORCID record for Adam R. Karpf
Martin Widschwendter
mDepartment of Women’s Cancer, Institute for Women’s Health, University College London, WC1E 6AU London, United Kingdom;
nResearch Institute for Biomedical Aging Research, Universität Innsbruck, 6020 Innsbruck, Austria;
oEuropean Translational Oncology Prevention and Screening (EUTOPS) Institute, Universität Innsbruck, 6060 Hall in Tirol, Austria;
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Anil K. Sood
pDepartment of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
qDepartment of Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
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Robert C. Bast Jr
rDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
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Andrew K. Godwin
sDepartment of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160;
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Kathy D. Miller
tDepartment of Medicine, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202
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  • For correspondence: kathmill@iu.edu c0035@dsmc.or.kr jaeyeonk@iu.edu
Chi-Heum Cho
cDepartment of Obstetrics and Gynecology, School of Medicine, Keimyung University, 41931 Daegu, Republic of Korea;
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  • For correspondence: kathmill@iu.edu c0035@dsmc.or.kr jaeyeonk@iu.edu
Jaeyeon Kim
aDepartment of Biochemistry and Molecular Biology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202;
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  • ORCID record for Jaeyeon Kim
  • For correspondence: kathmill@iu.edu c0035@dsmc.or.kr jaeyeonk@iu.edu
  1. Edited by R. Michael Roberts, University of Missouri, Columbia, MO, and approved October 12, 2020 (received for review June 30, 2020)

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Significance

Why women carrying a pathogenic germline BRCA1 mutation are predisposed to ovarian and breast cancer remains elusive. This study points to ovarian progesterone as a culprit. Generally, BRCA1-mutation carriers exhibit high yet individually varying levels of progesterone during the menstrual cycle. Although not all BRCA1-mutation carriers develop these cancers, all of them are advised to undergo prophylactic surgeries at a young age (under 40 y to 45 y) to prevent ovarian and breast cancer. Insights from robust in vivo findings in this study offer a novel concept: Targeting progesterone signaling with antiprogestins could be an effective nonsurgical prophylactic option for ovarian and breast cancer prevention for these high-risk women.

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.

  • progesterone
  • antiprogestins
  • hormone
  • ovarian cancer
  • BRCA

Footnotes

  • ↵1O.K. and E.Y.P. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: kathmill{at}iu.edu, c0035{at}dsmc.or.kr, or jaeyeonk{at}iu.edu.
  • Author contributions: J.K. designed research; O.K., E.Y.P., S.S., R.E.E., Y.-H.S., and D.M.C. performed research; F.J.D., J.P.L., S.M.H., and A.K.G. contributed new reagents/analytic tools; O.K., E.Y.P., S.Y.K., L.A.Q., D.-J.C., F.M.F., K.P.N., A.R.K., M.W., A.K.S., R.C.B., A.K.G., K.D.M., C.-H.C., and J.K. analyzed data; and J.K. wrote the paper with assistance from all authors.

  • 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.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2013595117/-/DCSupplemental.

Data Availability.

The RNA sequencing data have been deposited in Gene Expression Omnibus (GEO) (accession no. GSE157960).

Published under the PNAS license.

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References

  1. ↵
    1. S. A. Narod,
    2. W. D. Foulkes
    , BRCA1 and BRCA2: 1994 and beyond. Nat. Rev. Cancer 4, 665–676 (2004).
    OpenUrlCrossRefPubMed
  2. ↵
    1. M. C. King
    , “The race” to clone BRCA1. Science 343, 1462–1465 (2014).
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. R. Roy,
    2. J. Chun,
    3. S. N. Powell
    , BRCA1 and BRCA2: Different roles in a common pathway of genome protection. Nat. Rev. Cancer 12, 68–78 (2011).
    OpenUrlCrossRefPubMed
  4. ↵
    1. N. Mavaddat et al.; HEBON; EMBRACE; GEMO Study Collaborators; kConFab Investigators; SWE-BRCA Collaborators; Consortium of Investigators of Modifiers of BRCA1/2
    , Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol. Biomarkers Prev. 21, 134–147 (2012).
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. L. C. Hartmann,
    2. N. M. Lindor
    , The role of risk-reducing surgery in hereditary breast and ovarian cancer. N. Engl. J. Med. 374, 454–468 (2016).
    OpenUrlCrossRefPubMed
  6. ↵
    1. P. E. Lønning
    , Aromatase inhibitors in breast cancer. Endocr. Relat. Cancer 11, 179–189 (2004).
    OpenUrlAbstract
  7. ↵
    1. C. K. Osborne
    , Tamoxifen in the treatment of breast cancer. N. Engl. J. Med. 339, 1609–1618 (1998).
    OpenUrlCrossRefPubMed
  8. ↵
    1. I. E. Smith,
    2. M. Dowsett
    , Aromatase inhibitors in breast cancer. N. Engl. J. Med. 348, 2431–2442 (2003).
    OpenUrlCrossRefPubMed
  9. ↵
    1. W. D. Foulkes,
    2. I. E. Smith,
    3. J. S. Reis-Filho
    , Triple-negative breast cancer. N. Engl. J. Med. 363, 1938–1948 (2010).
    OpenUrlCrossRefPubMed
  10. ↵
    1. B. A. Heemskerk-Gerritsen et al.; Hereditary Breast and Ovarian Cancer Research Group Netherlands
    , Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: Revisiting the evidence for risk reduction. J. Natl. Cancer Inst. 107, djv033 (2015).
    OpenUrlCrossRefPubMed
  11. ↵
    1. J. Kotsopoulos et al.; Hereditary Breast Cancer Clinical Study Group
    , Bilateral oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers. J. Natl. Cancer Inst. 109, djw177 (2016).
    OpenUrl
  12. ↵
    1. S. M. Domchek et al
    ., Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 304, 967–975 (2010).
    OpenUrlCrossRefPubMed
  13. ↵
    1. S. A. Narod
    , Modifiers of risk of hereditary breast and ovarian cancer. Nat. Rev. Cancer 2, 113–123 (2002).
    OpenUrlCrossRefPubMed
  14. ↵
    1. M. Widschwendter et al
    ., The sex hormone system in carriers of BRCA1/2 mutations: A case-control study. Lancet Oncol. 14, 1226–1232 (2013).
    OpenUrlCrossRefPubMed
  15. ↵
    1. L. C. Peres et al
    ., Invasive epithelial ovarian cancer survival by histotype and disease stage. J. Natl. Cancer Inst. 111, 60–68 (2019).
    OpenUrlPubMed
  16. ↵
    1. K. R. Cho,
    2. IeM. Shih
    , Ovarian cancer. Annu. Rev. Pathol. 4, 287–313 (2009).
    OpenUrlCrossRefPubMed
  17. ↵
    1. R. C. Bast Jr,
    2. B. Hennessy,
    3. G. B. Mills
    , The biology of ovarian cancer: New opportunities for translation. Nat. Rev. Cancer 9, 415–428 (2009).
    OpenUrlCrossRefPubMed
  18. ↵
    1. D. D. Bowtell et al
    ., Rethinking ovarian cancer II: Reducing mortality from high-grade serous ovarian cancer. Nat. Rev. Cancer 15, 668–679 (2015).
    OpenUrlCrossRefPubMed
  19. ↵
    1. J. Kim et al
    ., Cell origins of high-grade serous ovarian cancer. Cancers (Basel) 10, 433 (2018).
    OpenUrl
  20. ↵
    1. Cancer Genome Atlas Network
    , Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).
    OpenUrlCrossRefPubMed
  21. ↵
    1. Cancer Genome Atlas Research Network
    , Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).
    OpenUrlCrossRefPubMed
  22. ↵
    1. T. R. Rebbeck et al.; CIMBA Consortium
    , Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA 313, 1347–1361 (2015).
    OpenUrlCrossRefPubMed
  23. ↵
    1. J. Kotsopoulos et al.; Hereditary Ovarian Cancer Clinical Study Group
    , Age-specific ovarian cancer risks among women with a BRCA1 or BRCA2 mutation. Gynecol. Oncol. 150, 85–91 (2018).
    OpenUrlPubMed
  24. ↵
    1. V. Beral,
    2. R. Doll,
    3. C. Hermon,
    4. R. Peto,
    5. G. Reeves; Collaborative Group on Epidemiological Studies of Ovarian Cancer
    , Ovarian cancer and oral contraceptives: Collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 371, 303–314 (2008).
    OpenUrlCrossRefPubMed
  25. ↵
    1. S. Iodice et al
    ., Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: A meta-analysis. Eur. J. Cancer 46, 2275–2284 (2010).
    OpenUrlCrossRefPubMed
  26. ↵
    1. K. K. Tsilidis et al
    ., Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European prospective investigation into cancer and nutrition. Br. J. Cancer 105, 1436–1442 (2011).
    OpenUrlCrossRefPubMed
  27. ↵
    1. N. Wentzensen et al
    ., Ovarian cancer risk factors by histologic subtype: An analysis from the Ovarian Cancer Cohort Consortium. J. Clin. Oncol. 34, 2888–2898 (2016).
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. J. Kim et al
    ., High-grade serous ovarian cancer arises from fallopian tube in a mouse model. Proc. Natl. Acad. Sci. U.S.A. 109, 3921–3926 (2012).
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. O. Kim et al
    ., In vivo modeling of metastatic human high-grade serous ovarian cancer in mice. PLoS Genet. 16, e1008808 (2020).
    OpenUrl
  30. ↵
    1. J. M. Piek et al
    ., BRCA1/2-related ovarian cancers are of tubal origin: A hypothesis. Gynecol. Oncol. 90, 491 (2003).
    OpenUrlCrossRefPubMed
  31. ↵
    1. C. P. Crum et al
    ., Lessons from BRCA: The tubal fimbria emerges as an origin for pelvic serous cancer. Clin. Med. Res. 5, 35–44 (2007).
    OpenUrlAbstract/FREE Full Text
  32. ↵
    1. R. J. Kurman,
    2. IeM. Shih
    , The origin and pathogenesis of epithelial ovarian cancer: A proposed unifying theory. Am. J. Surg. Pathol. 34, 433–443 (2010).
    OpenUrlCrossRefPubMed
  33. ↵
    1. R. Perets et al
    ., Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models. Cancer Cell 24, 751–765 (2013).
    OpenUrlCrossRefPubMed
  34. ↵
    1. R. Wu et al
    ., Impact of oviductal versus ovarian epithelial cell of origin on ovarian endometrioid carcinoma phenotype in the mouse. J. Pathol. 240, 341–351 (2016).
    OpenUrlCrossRef
  35. ↵
    1. D. Klinkebiel,
    2. W. Zhang,
    3. S. N. Akers,
    4. K. Odunsi,
    5. A. R. Karpf
    , DNA methylome analyses implicate fallopian tube epithelia as the origin for high-grade serous ovarian cancer. Mol. Cancer Res. 14, 787–794 (2016).
    OpenUrlAbstract/FREE Full Text
  36. ↵
    1. J. Kim,
    2. D. M. Coffey,
    3. L. Ma,
    4. M. M. Matzuk
    , The ovary is an alternative site of origin for high-grade serous ovarian cancer in mice. Endocrinology 156, 1975–1981 (2015).
    OpenUrlCrossRefPubMed
  37. ↵
    1. S. Zhang et al
    ., Both fallopian tube and ovarian surface epithelium are cells-of-origin for high-grade serous ovarian carcinoma. Nat. Commun. 10, 5367 (2019).
    OpenUrlCrossRef
  38. ↵
    1. N. D. Kauff et al
    ., Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: A multicenter, prospective study. J. Clin. Oncol. 26, 1331–1337 (2008).
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. N. A. Arango et al
    ., A mesenchymal perspective of Müllerian duct differentiation and regression in Amhr2-lacZ mice. Mol. Reprod. Dev. 75, 1154–1162 (2008).
    OpenUrlCrossRefPubMed
  40. ↵
    1. Y. Liu et al
    ., A mouse model that reproduces the developmental pathways and site specificity of the cancers associated with the human BRCA1 mutation carrier state. EBioMedicine 2, 1318–1330 (2015).
    OpenUrl
  41. ↵
    1. E. Lengyel
    , Ovarian cancer development and metastasis. Am. J. Pathol. 177, 1053–1064 (2010).
    OpenUrlCrossRefPubMed
  42. ↵
    1. C. J. Lord,
    2. A. Ashworth
    , BRCAness revisited. Nat. Rev. Cancer 16, 110–120 (2016).
    OpenUrlCrossRefPubMed
  43. ↵
    1. S. Dutta,
    2. P. Sengupta
    , Men and mice: Relating their ages. Life Sci. 152, 244–248 (2016).
    OpenUrlCrossRefPubMed
  44. ↵
    1. D. C. Smith,
    2. R. Prentice,
    3. D. J. Thompson,
    4. W. L. Herrmann
    , Association of exogenous estrogen and endometrial carcinoma. N. Engl. J. Med. 293, 1164–1167 (1975).
    OpenUrlCrossRefPubMed
  45. ↵
    1. J. J. Kim,
    2. T. Kurita,
    3. S. E. Bulun
    , Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Endocr. Rev. 34, 130–162 (2013).
    OpenUrlCrossRefPubMed
  46. ↵
    1. K. J. Hamilton,
    2. S. C. Hewitt,
    3. Y. Arao,
    4. K. S. Korach
    , Estrogen hormone biology. Curr. Top. Dev. Biol. 125, 109–146 (2017).
    OpenUrlCrossRefPubMed
  47. ↵
    1. J. P. Lydon et al
    ., Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 9, 2266–2278 (1995).
    OpenUrlAbstract/FREE Full Text
  48. ↵
    1. K. Garson,
    2. L. F. Gamwell,
    3. E. M. Pitre,
    4. B. C. Vanderhyden
    , Technical challenges and limitations of current mouse models of ovarian cancer. J. Ovarian Res. 5, 39 (2012).
    OpenUrlCrossRefPubMed
  49. ↵
    1. A. K. Nagaraja et al
    ., Deletion of Dicer in somatic cells of the female reproductive tract causes sterility. Mol. Endocrinol. 22, 2336–2352 (2008).
    OpenUrlCrossRefPubMed
  50. ↵
    1. G. Gonzalez,
    2. R. R. Behringer
    , Dicer is required for female reproductive tract development and fertility in the mouse. Mol. Reprod. Dev. 76, 678–688 (2009).
    OpenUrlCrossRefPubMed
  51. ↵
    1. R. Behringer,
    2. M. Gertsenstein,
    3. K. V. Nagy,
    4. A. Nagy
    , Administration of gonadotropins for superovulation in mice. Cold Spring Harb. Protoc. 2018, doi:10.1101/pdb.prot092403 (2018).
    OpenUrlAbstract/FREE Full Text
  52. ↵
    1. J. Kim et al
    ., Peroxisome proliferator-activated receptor gamma is a target of progesterone regulation in the preovulatory follicles and controls ovulation in mice. Mol. Cell. Biol. 28, 1770–1782 (2008).
    OpenUrlAbstract/FREE Full Text
  53. ↵
    1. B. G. Miller,
    2. D. T. Armstrong
    , Effects of a superovulatory dose of pregnant mare serum gonadotropin on ovarian function, serum estradiol, and progesterone levels and early embryo development in immature rats. Biol. Reprod. 25, 261–271 (1981).
    OpenUrlCrossRefPubMed
  54. ↵
    1. Y. W. Yun,
    2. B. H. Yuen,
    3. Y. S. Moon
    , Effects of superovulatory doses of pregnant mare serum gonadotropin on oocyte quality and ovulatory and steroid hormone responses in rats. Gamete Res. 16, 109–120 (1987).
    OpenUrlCrossRefPubMed
  55. ↵
    1. X. Li,
    2. B. W. O’Malley
    , Unfolding the action of progesterone receptors. J. Biol. Chem. 278, 39261–39264 (2003).
    OpenUrlFREE Full Text
  56. ↵
    1. F. Cadepond,
    2. A. Ulmann,
    3. E. E. Baulieu
    , RU486 (mifepristone): Mechanisms of action and clinical uses. Annu. Rev. Med. 48, 129–156 (1997).
    OpenUrlCrossRefPubMed
  57. ↵
    1. A. J. Poole et al
    ., Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science 314, 1467–1470 (2006).
    OpenUrlAbstract/FREE Full Text
  58. ↵
    1. P. Lee,
    2. D. G. Rosen,
    3. C. Zhu,
    4. E. G. Silva,
    5. J. Liu
    , Expression of progesterone receptor is a favorable prognostic marker in ovarian cancer. Gynecol. Oncol. 96, 671–677 (2005).
    OpenUrlCrossRefPubMed
  59. ↵
    1. W. Sieh et al
    ., Hormone-receptor expression and ovarian cancer survival: An ovarian tumor tissue analysis consortium study. Lancet Oncol. 14, 853–862 (2013).
    OpenUrlCrossRefPubMed
  60. ↵
    1. M. Aghmesheh et al
    ., Expression of steroid hormone receptors in BRCA1-associated ovarian carcinomas. Gynecol. Oncol. 97, 16–25 (2005).
    OpenUrlCrossRefPubMed
  61. ↵
    1. M. Pineda-Torres et al
    ., Evidence of an immunosuppressive effect of progesterone upon in vitro secretion of proinflammatory and prodegradative factors in a model of choriodecidual infection. BJOG 122, 1798–1807 (2015).
    OpenUrl
  62. ↵
    1. N. M. Shah,
    2. P. F. Lai,
    3. N. Imami,
    4. M. R. Johnson
    , Progesterone-related immune modulation of pregnancy and labor. Front. Endocrinol. (Lausanne) 10, 198 (2019).
    OpenUrl
  63. ↵
    1. D. Huang,
    2. D. A. Gaul,
    3. H. Nan,
    4. J. Kim,
    5. F. M. Fernández
    , Deep metabolomics of a high-grade serous ovarian cancer triple-knockout mouse model. J. Proteome Res. 18, 3184–3194 (2019).
    OpenUrl
  64. ↵
    1. H. A. Risch
    , Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J. Natl. Cancer Inst. 90, 1774–1786 (1998).
    OpenUrlCrossRefPubMed
  65. ↵
    1. F. Modugno et al
    ., Hormone response in ovarian cancer: Time to reconsider as a clinical target? Endocr. Relat. Cancer 19, R255–R279 (2012).
    OpenUrlAbstract/FREE Full Text
  66. ↵
    1. N. Y. Wu et al
    ., Progesterone prevents high-grade serous ovarian cancer by inducing necroptosis of p53-defective fallopian tube epithelial cells. Cell Rep. 18, 2557–2565 (2017).
    OpenUrl
  67. ↵
    1. J. F. Strauss III and
    2. R. L. Barbieri
    1. C. A. Schreiber,
    2. K. Barnhar
    , “Contraception”in Yen & Jaffe’s Reproductive Endocrinology, J. F. Strauss III and R. L. Barbieri, Eds. (Elsevier, ed. 8, 2019), pp. 962–978.
  68. ↵
    1. E. D. Albrecht,
    2. G. J. Pepe
    , Placental steroid hormone biosynthesis in primate pregnancy. Endocr. Rev. 11, 124–150 (1990).
    OpenUrlCrossRefPubMed
  69. ↵
    1. D. Thomas
    , Gene–environment-wide association studies: Emerging approaches. Nat. Rev. Genet. 11, 259–272 (2010).
    OpenUrlCrossRefPubMed
  70. ↵
    1. B. Vogelstein et al
    ., Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 319, 525–532 (1988).
    OpenUrlCrossRefPubMed
  71. ↵
    1. L. A. Torre et al
    ., Ovarian cancer statistics, 2018. CA: Can. J. Clin. 68, 284–296 (2018).
    OpenUrl
  72. ↵
    1. A. A. Jazaeri et al
    ., Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers. J. Natl. Cancer Inst. 94, 990–1000 (2002).
    OpenUrlCrossRefPubMed
  73. ↵
    1. R. L. Coleman et al
    ., Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N. Engl. J. Med. 381, 2403–2415 (2019).
    OpenUrlCrossRefPubMed
  74. ↵
    1. A. González-Martín et al.; PRIMA/ENGOT-OV26/GOG-3012 Investigators
    , Niraparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. J. Med. 381, 2391–2402 (2019).
    OpenUrlCrossRefPubMed
  75. ↵
    1. R. Chodankar et al
    ., Cell-nonautonomous induction of ovarian and uterine serous cystadenomas in mice lacking a functional Brca1 in ovarian granulosa cells. Curr. Biol. 15, 561–565 (2005).
    OpenUrlCrossRefPubMed
  76. ↵
    1. H. Hong et al
    ., Changes in the mouse estrus cycle in response to BRCA1 inactivation suggest a potential link between risk factors for familial and sporadic ovarian cancer. Cancer Res. 70, 221–228 (2010).
    OpenUrlAbstract/FREE Full Text
  77. ↵
    1. J. L. Walker et al
    ., Society of Gynecologic Oncology recommendations for the prevention of ovarian cancer. Cancer 121, 2108–2120 (2015).
    OpenUrlPubMed
  78. ↵
    1. M. H. Greene,
    2. P. L. Mai,
    3. P. E. Schwartz
    , Does bilateral salpingectomy with ovarian retention warrant consideration as a temporary bridge to risk-reducing bilateral oophorectomy in BRCA1/2 mutation carriers? Am. J. Obstet. Gynecol. 204, 19.e1–19.e6 (2011).
    OpenUrlCrossRefPubMed
  79. ↵
    1. E. Rosato,
    2. M. Farris,
    3. C. Bastianelli
    , Mechanism of action of ulipristal acetate for emergency contraception: A systematic review. Front. Pharmacol. 6, 315 (2016).
    OpenUrl
  80. ↵
    1. K. B. Horwitz,
    2. Y. Koseki,
    3. W. L. McGuire
    , Estrogen control of progesterone receptor in human breast cancer: Role of estradiol and antiestrogen. Endocrinology 103, 1742–1751 (1978).
    OpenUrlCrossRefPubMed
  81. ↵
    1. C. Davies et al.; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
    , Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: Patient-level meta-analysis of randomised trials. Lancet 378, 771–784 (2011).
    OpenUrlCrossRefPubMed
  82. ↵
    1. Y. Li et al
    ., Clinicopathological characteristics and breast cancer-specific survival of patients with single hormone receptor-positive breast cancer. JAMA Netw. Open 3, e1918160 (2020).
    OpenUrl
  83. ↵
    1. S. P. Langdon et al
    ., Functionality of the progesterone receptor in ovarian cancer and its regulation by estrogen. Clin. Cancer Res. 4, 2245–2251 (1998).
    OpenUrlAbstract
  84. ↵
    1. C. Trope,
    2. C. Marth,
    3. J. Kaern
    , Tamoxifen in the treatment of recurrent ovarian carcinoma. Eur. J. Cancer 36 (suppl. 4), S59–S61 (2000).
    OpenUrl
  85. ↵
    1. C. Brisken et al
    ., A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc. Natl. Acad. Sci. U.S.A. 95, 5076–5081 (1998).
    OpenUrlAbstract/FREE Full Text
  86. ↵
    1. E. Nolan et al.; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab)
    , RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat. Med. 22, 933–939 (2016).
    OpenUrlCrossRefPubMed
  87. ↵
    1. V. Boonyaratanakornkit,
    2. D. P. Edwards
    , Receptor mechanisms mediating non-genomic actions of sex steroids. Semin. Reprod. Med. 25, 139–153 (2007).
    OpenUrlCrossRefPubMed
  88. ↵
    1. K. Lei et al
    ., Progesterone acts via the nuclear glucocorticoid receptor to suppress IL-1β-induced COX-2 expression in human term myometrial cells. PLoS One 7, e50167 (2012).
    OpenUrlCrossRefPubMed
  89. ↵
    1. P. Horby et al
    ., Dexamethasone in hospitalized patients with covid-19–Preliminary report. N. Engl. J. Med., doi:10.1056/NEJMoa2021436 (2020).
    OpenUrlCrossRefPubMed
  90. ↵
    1. C. Brisken
    , Progesterone signalling in breast cancer: A neglected hormone coming into the limelight. Nat. Rev. Cancer 13, 385–396 (2013).
    OpenUrlCrossRefPubMed
  91. ↵
    1. M. C. King,
    2. J. H. Marks,
    3. J. B. Mandell; New York Breast Cancer Study Group
    , Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302, 643–646 (2003).
    OpenUrlAbstract/FREE Full Text
  92. ↵
    1. J. Kotsopoulos et al.; Hereditary Breast Cancer Clinical Study Group
    , Hormone replacement therapy after oophorectomy and breast cancer risk among BRCA1 mutation carriers. JAMA Oncol. 4, 1059–1065 (2018).
    OpenUrl
  93. ↵
    1. G. L. Anderson et al.; Women’s Health Initiative Investigators
    , Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: The Women’s Health Initiative randomized trial. JAMA 290, 1739–1748 (2003).
    OpenUrlCrossRefPubMed
  94. ↵
    1. G. L. Anderson et al.; Women’s Health Initiative Steering Committee
    , Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA 291, 1701–1712 (2004).
    OpenUrlCrossRefPubMed
  95. ↵
    1. G. L. Anderson et al
    ., Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: Extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 13, 476–486 (2012).
    OpenUrlCrossRefPubMed
  96. ↵
    1. J. E. Manson et al.; WHI Investigators
    , Menopausal hormone therapy and long-term all-cause and cause-specific mortality: The Women’s Health Initiative randomized trials. JAMA 318, 927–938 (2017).
    OpenUrlCrossRefPubMed
  97. ↵
    1. M. Dhont
    , History of oral contraception. Eur. J. Contracept. Reprod. Heal. Care 15 (suppl. 2), S12–S18 (2010).
    OpenUrl
  98. ↵
    1. R. Rivera,
    2. I. Yacobson,
    3. D. Grimes
    , The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices. Am. J. Obstet. Gynecol. 181, 1263–1269 (1999).
    OpenUrlCrossRefPubMed
  99. ↵
    1. W. G. Rossmanith,
    2. D. Steffens,
    3. G. Schramm
    , A comparative randomized trial on the impact of two low-dose oral contraceptives on ovarian activity, cervical permeability, and endometrial receptivity. Contraception 56, 23–30 (1997).
    OpenUrlPubMed
  100. ↵
    1. D. R. Mishell Jr,
    2. I. H. Thorneycroft,
    3. R. M. Nakamura,
    4. Y. Nagata,
    5. S. C. Stone
    , Serum estradiol in women ingesting combination oral contraceptive steroids. Am. J. Obstet. Gynecol. 114, 923–928 (1972).
    OpenUrlPubMed
  101. ↵
    1. A. Lukanova,
    2. R. Kaaks
    , Endogenous hormones and ovarian cancer: Epidemiology and current hypotheses. Cancer Epidemiol. Biomarkers Prev. 14, 98–107 (2005).
    OpenUrlAbstract/FREE Full Text
  102. ↵
    1. K. Gemzell-Danielsson,
    2. C. X. Meng
    , Emergency contraception: Potential role of ulipristal acetate. Int. J. Womens Health 2, 53–61 (2010).
    OpenUrlPubMed
  103. ↵
    1. B. J. Attardi,
    2. J. Burgenson,
    3. S. A. Hild,
    4. J. R. Reel
    , In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone. J. Steroid Biochem. Mol. Biol. 88, 277–288 (2004).
    OpenUrlCrossRefPubMed

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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, Andrew K. Godwin, Kathy D. Miller, Chi-Heum Cho, Jaeyeon Kim
Proceedings of the National Academy of Sciences Dec 2020, 117 (50) 31993-32004; DOI: 10.1073/pnas.2013595117

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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, Andrew K. Godwin, Kathy D. Miller, Chi-Heum Cho, Jaeyeon Kim
Proceedings of the National Academy of Sciences Dec 2020, 117 (50) 31993-32004; DOI: 10.1073/pnas.2013595117
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