A Genetic and Metabolic Basis for Hormonally Driven Postmenopausal Breast Cancer
Abstract
High estrogen exposure is a risk factor for the development of breast cancer. However, there is no clear link that tells us which genes inherited from one s parents are responsible for generating different amounts of estrogens and thus are responsible for increased breast cancer risk. Before menopause, the majority of estrogens come from the ovaries. After menopause, the adrenal gland makes steroids (i.e., DHEA) that can be converted to estrogens in the breast and other tissues. Aromatase is an enzyme that is required for making estrogens from DHEA. The enzyme 3-beta-hydroxysteroid dehydrogenase-1 (3-beta-HSD1) is encoded by the gene HSD3B1. It works one step prior to aromatase s action in making estrogens and is absolutely required to convert DHEA to estrogens in postmenopausal women. Two forms of the HSD3B1 gene exist. One makes a slow enzyme and the other makes a fast enzyme that more rapidly makes estrogens. Further, the fast enzyme is present much more frequently in White compared to Black women. We hypothesize overall that inheritance of the fast vs. slow enzyme regulates the conversion of DHEA to estrogens in postmenopausal women. The overall objective of this project is to perform a prospective clinical study to determine (1) whether inheritance of the gene for the fast enzyme is a risk factor for the development of estrogen-dependent and estrogen receptor (ER)-positive (+) breast cancer in postmenopausal women, (2) whether the gene is responsible, at least in part, for the known differences in the proportion of ER+ vs. ER-negative breast cancer cases in White vs. Black women, (3) whether this gene predicts which women with ER+ breast cancer have better responses to aromatase inhibitors, a standard treatment for ER+ breast cancer, and (4) identify a way to inhibit the fast 3-beta-HSD1 enzyme so that estrogen production is slowed. This proposal addresses the overarching challenges of (1) preventing breast cancer, (2) identifying determinants of breast cancer initiation, risk, or susceptibility, and (3) identifying what drives breast cancer growth in order to determine how to stop it. We anticipate that this work will benefit women at risk for breast cancer by way of developing new prevention strategies to block the development of breast cancer. Furthermore, we expect that it will benefit women with breast cancer because it will present a new opportunity for developing personalized approaches to treatment. Yet another benefit is a reduction in the cost of therapy by, for example, identifying who may benefit from aromatase inhibitor treatment alone. We anticipate no risks. Perhaps most importantly, we anticipate that patients will experience clinical benefit immediately after the study is completed because our work in prostate cancer has led to the development of clinically available tests for determining HSD3B1 genotype. Finally, we anticipate that preventative strategies that come from our proposal will help reduce and ultimately end breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210082
Entities
People
- Nima Sharifi
Organizations
- Cleveland Clinic
- United States Army