Epigenetic Modulation of SOS1 Gene Promotes Breast Cancer Disparity by Altering Immune Landscape
Abstract
Which overarching challenge(s) does this research address? In the US, more than 40,000 breast cancer patients succumb to this disease every year. The age-adjusted breast cancer incidence in African American (AA) women is lower compared to Caucasian (CA) women. However, the mortality rate of AA women was 29.5 while the rate of CA women was 20.8. Thus, the cancer death rate in AA females is 14% higher than in CA female. Furthermore, AA women have a higher incidence of the most aggressive subtype, known as triple-negative breast cancer, than other racial and ethnic groups. However, exact reasons to explain this racial disparity are still yet poorly understood. The goal of the current proposal is to find genetic and non-genetic factors that influence the disease process that is specific to AA women so that we can identify the exact target to treat and prevent the aggressive breast cancer in this population. Therefore, this project addresses the Overarching Challenge “Identify determinants of breast cancer initiation, risk, or susceptibility” and “Identify what drives breast cancer growth; determine how to stop it”. We also identified a compound that targets the pathway specific to AA patients, and we expect this compound can be used for prevention of tumor metastasis among AA patients. Accordingly, this project also addresses “Eliminate the mortality associated with metastatic breast cancer.” We do believe that the proposed hypothesis, if proven to be valid, presents a novel paradigm that significantly impacts the treatment and prevention of breast cancer. We hypothesize that AA women with obesity develop aggressive breast cancer by upregulation of the gene called SOS1 gene through race/ethnic-specific non-genetic control and also by tiny RNA called miR-483. These change eventually promote tumor cell growth and also alter immune system of patients. We also hypothesize that our identified compound called taxifolin and its modified chemical (TF-10) selectively suppress the proposed pathway, thereby preventing lung metastasis of breast cancer. We will (i) figure out how this SOS1 gene is regulated in an AA-specific manner, (ii) how this gene promote metastatic disease, and (iii) test the efficacy of taxifolin in specific animal models. What types of patients will it help and how will it help them? We are developing preventive drugs that are effective to AA breast cancer patients with obesity. What are the potential clinical applications, benefits, and risks? We plan to bring our drug eventually to a clinical trial to see the preventive effect on breast cancer patients in AA women with obesity. These patients are likely to get benefits. What is the projected time it may take to achieve a patient-related outcome? We design to complete the proposed experiments in 3 years. We will then move to a clinical trial, which may take as long as 5 years to obtain initial results. What is the likely impact of this study on the BCRP’s mission of ending breast cancer? The goal of this project is to develop a preventive and therapeutic drug specific to AA women with obesity who experience high mortality rate of breast cancer. We already have a lead compound and are testing the efficacy in relevant animal model. Therefore, this project is strongly in line with BCRP’s mission of ending breast cancer. If the research is too basic for clinical applicability, describe the interim outcomes. Although our project is strongly translational and we already identified a lead compound to prevent breast cancer in AA women with obesity, the research still takes time and we plan to initiate our clinical trial within 3 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110075
Entities
People
- Kounosuke Watabe
Organizations
- United States Army
- Wake Forest University