Cell-Based Memory of DNA Damage in Breast Cancer
Abstract
Although there is a large range of cancer phenotypes, observed even among breast cancers, it has often been proposed that most or all cancers share a basic mechanism of progression to malignancy. A popular carcinogenesis model framework divides the progression into three stages: initiation, promotion and progression. In the earliest stages, comprising initiation, cells are thought to shift into a physiological state that is predisposed to developing the mutations and characteristics necessary for malignancy. The events of initiation - whether they are similar for all cancers or not - likely hold the key to truly understanding how and why normal cells become cancerous. It is at the step of initiation that many anticarcinogenic compounds are thought to act. However, the process of initiation has been hard to study because of our inability to identify cells that can eventually become cancerous very early in the process and track them over time. The long-term goal of the research program is to define in detail the genetic and epigenetic changes in initiated cells that, over time, confer a predisposition to malignancy. We proposed to take a novel approach to this problem by building and characterizing a synthetic transcription-based memory circuit that will allow us to mark and track the lineages of single cells that have suffered transient DNA damage. For this proposal, we had two goals: (1) to construct a tunable mammalian cell-based memory device; and (2) to establish a genetic circuit to permanently record the experience of a transient DNA damaging event in a damaged cell and its progeny, and to use the output to collect specific cells for long-term tracking of phenotypic change. We made substantial progress on both Aims.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2009
- Accession Number
- ADA520048
Entities
People
- Pamela Silver
Organizations
- Harvard Medical School