Identification of Early Contributors to BRCA1-Mutation-Driven Breast Cancer
Abstract
Objective: The overall aim of this proposal is to identify early determinants of breast cancer initiation, risk, or susceptibility. Women with mutation in the BRCA1 gene (BRCA1+/-) are at increased risk for developing breast cancer (~70%-80% lifetime risk). We do not understand why and when cells with BRCA1 mutation start their progression towards cancer. Analysis of breast tumors arising in BRCA1 mutation carriers has revealed that their tumor cells carry thousands of mutations and in many different genes. However, it has been difficult to tell which of these mutations are important for tumor initiation. An insight into which genetic changes drive these ostensibly "normal" cells in BRCA1 mutation carriers to become tumor cells will be an important step towards designing mechanism-based breast cancer preventive strategies. The screens described in this proposal will address this question and will provide the means to identify critical early genetic changes that potentially drive breast cancer initiation in breast cells of women with mutation in BRCA1 gene. Rationale: The rationale for this proposal is based on the following observations: (1) Cells from BRCA1 mutation carriers (BRCA1+/- cells) are sensitive to one particular type of DNA damage that leads to replication stress, a cancer-promoting event (published work from our group). (2) This form of DNA damage (replication stress) is a well-established player in tumor formation. (published work from other groups). (3) In BRCA1+/-,p53+/- mice (mice with one mutated copy of BRCA1 and one mutated copy of p53), replication stress leads to tumor formation (unpublished work from our group). These observations indicate that (a) replication stress can cause cancer and (b) BRCA1+/- cells are sensitive to replication stress. Given that replication stress is one of the most common events occurring in cells undergoing cell division (like those in the breast), these presumably healthy/normal cells from BRCA1 mutation carriers must acquire the ability to survive in presence with replication stress in order to become tumor cells. The work proposed here will identify genes and pathways that are altered in "normal" breast cells of BRCA1 mutation carriers to allow these cells to tolerate replication stress. Such genetic changes could be the first step(s) that occur in the path to tumor formation. We are uniquely placed to test this hypothesis given our collection of breast cells derived from BRCA1 mutation carriers, our understanding of BRCA1 s role in DNA damage repair, published and preliminary data on BRCA1 and replication stress (RS), and the opportunity to work with collaborators at the Dana-Farber Cancer Institute (DFCI) and The Broad Institute/MIT, who are leaders in carrying out and analyzing such genome-scale screens. Clinical Implications: Once these genes have been identified through CRISPR and ORFeome-based screens, we will validate the top candidate genes by studies in cells and mice. This analysis will allow us to characterize what role these genes play in breast cancer initiation. We will also compare our top candidate genes (identified through the screens) with the current tumor database at DFCI and other institutes, to ask whether any of our candidate genes are also present in the tumors of BRCA1 mutation carriers. Any such evidence will provide further validation to the role these novel gene(s) and/or pathways play in breast cancer initiation. Importantly, the tumors that arise in BRCA1 mutation carriers are triple-negative, which is the hardest subset of sporadic breast cancer to treat. Insights from studying the cells of BRCA1 mutation carriers may also help in understanding initiation of triple-negative breast cancer. Having more information about how breast tumors are initiated can guide efforts aimed at prevention and also help in identification of vulnerabilities in established cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710024
Entities
People
- Shailja Pathania
Organizations
- Dana–Farber Cancer Institute
- United States Army