Defining High-Risk Precursor Signaling to Advance Breast Cancer Risk Assessment and Prevention
Abstract
Background: Making a major impact on the incidence and lethality of breast cancer will require more effective approaches for breast cancer risk assessment and prevention. These goals will not be met without a detailed understanding of the earliest tissue changes that ultimately drive the process of breast cancer development. While laboratory models can provide some information regarding this process, there is no substitute for the ability to define and understand the early, premalignant changes as they occur in women who are breast cancer-predisposed. One group of women at high breast cancer risk (up to 80% lifetime breast cancer risk) are those who have inherited mutations in the BRCA1 and BRCA2 genes. Currently, the only way these women can eliminate their risk is to undergo bilateral mastectomy before developing cancer. This breast tissue is normally discarded, but with the generous participation of these patients, we have established an Institutional Review Board-approved protocol that allows us to collect and analyze a portion of this tissue. Here, we propose detailed functional and molecular analysis of these tissues in order to reveal critical early steps in breast cancer development. We will then test how reversing these changes can prevent breast cancer in well-established animal models. These studies are likely to lead directly to clinical trials of new approaches to prevent breast cancer. Overarching Challenges: This proposal addresses three challenges defined in the Breakthrough Award Program Announcement: (1) Preventing breast cancer from occurring (primary prevention). (2) Identifying what makes the breast susceptible to cancer development. (3) Determining why some, but not all, women get breast cancer. Hypotheses and Objectives: Our previous work and our preliminary data suggest that the earliest changes leading to breast cancer in high-risk women involve abnormal signaling between different cell populations in the breast. Thus, our objectives are to reveal the functional abnormalities of these cells and to discover the deregulated pathways that sustain them. Then we will test the effect of blocking this abnormal signaling using validated model systems. This work will provide proof-of-principle for clinical trials of new and more effective approaches for breast cancer prevention. Study Design: In Aim 1, we will follow up our preliminary data showing abnormal cell populations in the breast tissues of women who are BRCA1/2 mutation carriers compared to tissues of control women who do not carry these mutations. We have developed technologies to isolate these abnormal cells and to perform detailed analysis of their abnormal properties. In Aim 2, we will discover the cause of these abnormal properties by carrying out a comprehensive analysis of gene expression and mutation in these specific breast cells from BRCA1/2 mutation carriers compared to controls. In Aim 3, we will test the effect of reversing abnormal signaling on breast cancer development using well-established cell-based and animal breast cancer models. Impact and Time Frame: Earlier detection and better treatment of breast cancer are important goals, but they are no substitute for effective breast cancer prevention. By identifying for the first time the early changes in tissues of high-risk women, we are likely to find new targets for breast cancer risk prediction and prevention. Testing the effect of reversing these changes as we propose herein should pave the way for near-term clinical trials of these approaches in high-risk women. Within 5 years, such clinical trials of new breast cancer preventatives could successfully reverse the early premalignant changes that we have identified in these women. Ultimately, ending breast cancer will require the type of systematic and detailed method we propose for discovering new prevention approaches.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510045
Entities
People
- Leif W Ellisen
Organizations
- Massachusetts General Hospital
- United States Army