Damaged Progenitors as Targets for Breast Cancer 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, pre-malignant 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. Through the support of our original Breakthrough proposal, we carried out molecular analysis of these tissues. This study revealed the striking presence of breast cells that had already suffered substantial DNA damage, even when the tissue looked microscopically normal. This paradigm-shifting finding suggests that expanding the study of this damaged subpopulation may reveal unanticipated and highly effective new approaches to eliminate such cells for breast cancer prevention. Overarching Challenges: This proposal addresses two challenges: (1) Prevent breast cancer (primary prevention). (2) Identify determinants of breast cancer initiation, risk, and susceptibility. Hypotheses and Objectives: Our Breakthrough-funded work identified a subpopulation of DNA-damaged cells that represent the earliest pre-cancerous precursors. We therefore hypothesize (1) that discovering markers defining this cell population will propel the development of new tissue-based predictors of breast cancer risk and (2) that this damaged subpopulation is likely to have specific therapeutic vulnerabilities that could be exploited to eliminate these cells. Accordingly, our objectives are to unravel the mechanisms that give rise to the damaged cells and to reveal specific methods for eliminating them, thereby laying the groundwork for clinical trials of novel breast cancer prevention approaches. Study Design: In Aim 1, we will dissect the molecular mechanism and consequences of failed DNA damage responses and repair in primary human BRCA1 and BRCA2 mutant breast tissues, obtained with the signed informed consent of our patients as in our prior Breakthrough-funded studies. Based on the findings, we will then test the ability of select therapeutic inhibitors to eliminate damaged precursor cells. In Aim 2, we will use new technologies to reveal and characterize such abnormal cell subpopulations of BRCA1 and BRCA2 mutant epithelia at the level of individual cells. These studies can unveil both tissue-based breast cancer risk markers and new approaches for targeting such cells. Finally, in Aim 3 we will employ high-throughput drug-screening approaches on primary cell cultures from BRCA1/2 mutant tissues and controls, systematically testing for unanticipated vulnerabilities of damaged precursor cells. Testing large numbers of such patient-derived tissues will provide high power to reveal sensitivities that are specific to the respective mutant tissues and are not confounded by patient-to-patient variability. Impact and Timeframe: Earlier detection and better treatment of breast cancer are important goals, but they are no substitute for effective breast cancer prevention. By successfully identifying for the first time the early changes in tissues of high-risk women, we are now on the path to finding new targets for breast cancer risk prediction and prevention. Testing a new way of revers
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910750
Entities
People
- Leif W Ellisen
Organizations
- Massachusetts General Hospital
- United States Army