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Edited by R. Michael Roberts, University of Missouri, Columbia, MO, and approved October 12, 2020 (received for review June 30, 2020)
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.
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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Targeting progesterone signaling prevents metastatic ovarian cancer
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