Targeting progesterone signaling prevents metastatic ovarian cancer

被引：34

作者：

Kim, Olga ^{[1
]}

Park, Eun Young ^{[1
]}

Kwon, Sun Young ^{[2
]}

Shin, Sojin ^{[3
]}

Emerson, Robert E. ^{[4
]}

Shin, Yong-Hyun ^{[1
]}

DeMayo, Francesco J. ^{[5
]}

Lydon, John P. ^{[6
]}

Coffey, Donna M. ^{[7
,8
]}

Hawkins, Shannon M. ^{[9
]}

Quilliam, Lawrence A. ^{[1
]}

Cheon, Dong-Joo ^{[10
]}

Fernandez, Facundo M. ^{[11
]}

Nephew, Kenneth P. ^{[12
]}

Karpf, Adam R. ^{[13
]}

Widschwendter, Martin ^{[14
,15
,16
]}

Sood, Anil K. ^{[17
,18
]}

Bast, Robert C., Jr. ^{[19
]}

Godwin, Andrew K. ^{[20
]}

Miller, Kathy D. ^{[21
]}

Cho, Chi-Heum ^{[3
]}

Kim, Jaeyeon ^{[1
]}

机构：

[1] Indiana Univ Sch Med, Indiana Univ, Melvin & Bren Simon Comprehens Canc Ctr, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

[2] Keimyung Univ, Sch Med, Dept Pathol, Daegu 41931, South Korea

[3] Keimyung Univ, Sch Med, Dept Obstet & Gynecol, Daegu 41931, South Korea

[4] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA

[5] NIEHS, Reprod & Dev Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA

[6] Baylor Coll Med, Dept Mol & Cell Biol, Houston, TX 77030 USA

[7] Houston Methodist, Dept Pathol & Genom Med, Houston, TX 77030 USA

[8] Weill Cornell Med Coll, Houston, TX 77030 USA

[9] Indiana Univ Sch Med, Indiana Univ, Melvin & Bren Simon Comprehens Canc Ctr, Dept Obstet & Gynecol, Indianapolis, IN 46202 USA

[10] Albany Med Coll, Dept Regenerat & Canc Cell Biol, Albany, NY 12208 USA

[11] Georgia Inst Technol, Sch Chem & Biochem, Atlanta, GA 30332 USA

[12] Indiana Univ Sch Med, Med Sci Program, Bloomington, IN 47405 USA

[13] Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Eppley Inst Canc Res, Omaha, NE 68198 USA

[14] UCL, Inst Womens Hlth, Dept Womens Canc, London WC1E 6AU, England

[15] Univ Innsbruck, Res Inst Biomed Aging Res, A-6020 Innsbruck, Austria

[16] Univ Innsbruck, European Translat Oncol Prevent & Screening EUTOP, A-6060 Hall In Tirol, Austria

[17] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA

[18] Univ Texas MD Anderson Canc Ctr, Dept Reprod Med, Houston, TX 77030 USA

[19] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA

[20] Univ Kansas, Dept Pathol & Lab Med, Med Ctr, Kansas City, KS 66160 USA

[21] Indiana Univ Sch Med, Indiana Univ, Melvin & Bren Simon Comprehens Canc Ctr, Dept Med, Indianapolis, IN 46202 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2020年 / 117卷 / 50期

基金：

欧洲研究理事会;

关键词：

progesterone; antiprogestins; hormone; ovarian cancer; BRCA; BRCA2 MUTATION CARRIERS; MARE SERUM GONADOTROPIN; ORAL-CONTRACEPTIVE USE; RISK-REDUCING SURGERY; BREAST-CANCER; FALLOPIAN-TUBE; AROMATASE INHIBITORS; POSTMENOPAUSAL WOMEN; HEREDITARY BREAST; HORMONE-RECEPTORS;

D O I：

10.1073/pnas.2013595117

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 (similar to 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.

引用

页码：31993 / 32004

页数：12

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