Systematic Identification, Validation, and Evaluation of Breast Cancer Risk Genes Through Follow-Up of Genome-Wide Association Studies
Abstract
This application addresses the overarching challenge: “Identify determinants of breast cancer initiation, risk, or susceptibility.” Rationale: Although we have made much progress in our understanding of the genetic changes that occur within the tumors that drive breast cancer, we still have a very limited understanding of why only some women develop the disease. A small proportion of women are at risk of breast cancer because of the mutations they have inherited from their parents (for example, in the BRCA1 or BRCA2 genes), but we have shown that every woman in the population is likely to carry genetic variants that can slightly influence her risk of cancer. Although the effect of each variant is small, the opportunity for furthering our understanding of the genetic and molecular mechanisms underlying breast cancer risk, and therefore for developing new risk reduction medications or treatments, is enormous. Proof of principle of this approach comes from our finding that common genetic variants near the estrogen receptor gene can slightly alter a woman’s breast cancer risk and that one of the best breast cancer treatments (for estrogen receptor positive cancers) is tamoxifen, which targets the estrogen receptor. Importantly, tamoxifen can be used both for treating breast cancer and reducing the risk of a second cancer, regardless of the genetic variants a woman carries at the estrogen receptor gene. However, tamoxifen is not a popular choice as a risk reduction medication, even in BRCA1/2 mutation carriers, because of its side effects (including an increased risk of other cancers). There is therefore an urgent need to better understand the determinants of breast cancer risk and to develop safe and effective risk reduction medications, as well as better treatments, particularly for estrogen receptor negative tumors. Objective: By studying about 119,000 breast cancer cases and 101,000 unaffected women, we have identified about 1,000 genes that we predict might contribute to risk of breast cancer. We predict that this list of candidates contains genes that drive breast cancer and could be used as targets for development of drugs to treat, and potentially prevent, breast cancer. However, identifying which of these candidates is a true breast cancer gene is challenging. Here we propose to use a comprehensive, unbiased approach and to measure the ability of all of these candidate genes to promote breast cancer. Aim 1: To identify breast cancer risk genes that upon knockout or activation promote proliferation, immortalization or DNA repair of breast cell lines in the laboratory. Aim 2: To identify breast cancer risk genes that upon knockout or activation promote tumor growth of immortalized human mammary epithelial cell lines in immune compromised mice. Aim 3: To start to define how these breast cancer risk genes work, and identify drugs that can modulate the proteins that they make. Aim 4: To demonstrate that the breast cancer risk genes we identify in the knockout experiments are the direct targets of genetic variants we know are associated with breast cancer risk. We anticipate that the outcome of these experiments will enhance our understanding of genes that induce breast cancer susceptibility and lead to the identification of new targets that will be used in future studies for developing new breast cancer risk reduction medications and treatments for all women. The timeline for successful translation of our project will depend on whether we identify genes that can be targeted with safe drugs already in use for other diseases or whether we will need to develop new drugs. If drug “repositioning” is successful, the timeline could be as short at 5 years to get into clinical trials, but our approach of targeting genes involved in breast cancer risk does provide the possibility of eventually reducing breast cancer incidence, as well as deaths from breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910116
Entities
People
- Joseph Rosenbluh
Organizations
- Monash University
- United States Army