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Published on: August 28, 2018
Targeting progesterone signaling prevents metastatic ovarian cancer
Olga Kim1, Eun Young Park1, Sun Young Kwon2
1Department of Biochemistry and Molecular Biology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202.
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.
Insights
Ovarian progesterone drives high-grade serous carcinoma (HGSC) development and metastasis. Blocking progesterone signaling with mifepristone or PR deletion suppressed HGSC and improved survival, suggesting a new prevention strategy.
Area of Science:
- Gynecologic Oncology
- Cancer Biology
- Endocrinology
Background:
- High-grade serous carcinoma (HGSC) is the most common and lethal ovarian cancer subtype.
- Effective cancer prevention strategies are needed, particularly for high-risk populations.
- Endogenous factors critical to HGSC initiation and progression remain to be fully elucidated.
Purpose of the Study:
- To identify crucial endogenous factors driving HGSC development and metastasis.
- To evaluate the therapeutic potential of targeting progesterone signaling in HGSC.
- To assess the efficacy of mifepristone and progesterone receptor (PR) deletion in a preclinical HGSC model.
Main Methods:
- Utilized a mouse model of high-grade serous carcinoma.
- Administered the pharmacologic progesterone inhibitor mifepristone.
- Genetically deleted the progesterone receptor (PR) in the mouse model.
- Assessed HGSC primary tumor development and peritoneal metastasis.
- Monitored mouse survival rates.
Main Results:
- Ovarian progesterone was identified as a critical endogenous factor promoting HGSC development.
- Blocking progesterone signaling via mifepristone or PR deletion significantly suppressed HGSC progression and metastasis.
- Mifepristone treatment led to a profound improvement in mouse survival, equivalent to approximately 18 human years.
Conclusions:
- Progesterone signaling is a key driver of HGSC initiation and progression.
- Targeting the progesterone/PR pathway represents a promising chemopreventive strategy for HGSC.
- This approach may be particularly beneficial for women with BRCA mutations, who are at high risk for HGSC.
