Deciphering the Role of Progesterone in Ovarian Cancer Risk for BRCA Mutation Carriers
Abstract
Women who inherit a deleterious BRCA1 or 2 mutation are prone to developing ovarian and breast cancer. While ovarian cancer occurs in fewer than 2 women among 100 without these mutations, 10 to 60 women among 100 BRCA1/2-mutation carriers develop ovarian cancer during their lifetimes. Because of this high genetic risk of ovarian cancer, BRCA1/2 carriers are advised to undergo prophylactic surgical removal of the ovaries and fallopian tubes at age 35 to 45 years to reduce ovarian cancer risk. Despite the high risk, however, not all BRCA1/2 carriers develop ovarian cancer. A significant number of BRCA1/2 carriers (40-90%) will not develop ovarian cancer. Yet, as there is no means to predict who will actually develop ovarian cancer among these BRCA carriers, all of them are subject to the prophylactic surgery in their premenopausal years, which leads to surgical menopause. Our recent study indicates that the steroid hormone progesterone released during the menstrual cycle is likely a vital intrinsic factor raising ovarian cancer risk and determining the ultimate development of ovarian cancer in BRCA carriers. Crucially, we showed that blocking the effects of progesterone with an antiprogestin (mifepristone: FDA-approved drug) prevented ovarian cancer development and markedly extended mouse survival (by ~18 human years). Supporting the importance of progesterone in ovarian cancer risk, a clinical study showed that the average menstrual progesterone level in BRCA1/2 carriers was 121% higher than in non-carriers. Additionally, 59% of these carriers exhibited progesterone levels above the top 75th percentile level of non-carriers. Thus, BRCA1/2 carriers have high yet individually varying levels of progesterone during their menstrual cycles. These clinical findings, as well as our mouse and human studies, lead us to hypothesize that menstrual progesterone levels may be a pivotal intrinsic factor in determining individual ovarian cancer risks among BRCA1/2 carriers and that antiprogestins can reduce or prevent ovarian cancer risk in high-risk women. In the proposed research, we will examine genetic and metabolomic abnormalities that may influence or affect steroid hormone synthesis and response among BRCA1/2 carriers, which can lead to the discovery of biomarkers enabling individual risk prediction. In addition, we will conduct mouse studies to assess a critical time window for effective antiprogestin prevention, which aids in determining the shortest effective duration of antiprogestin therapy for BRCA1/2 carriers. Defining progesterone as a crucial intrinsic factor that determines ovarian cancer risk will lay a foundation for predicting individual cancer risks and for establishing an effective, safe, nonsurgical option for risk reduction or prevention of this deadly malignancy in BRCA/1/2 carriers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210390
Entities
People
- Jaeyeon Kim
Organizations
- Indiana University
- United States Army