Investigating the Role of Aneuploidy in Breast Cancer
Abstract
DNA encodes genes, which provide a “blueprint” for cellular form and function. DNA is organized into discrete units known as “chromosomes.” Most cells in the human body contain a “balanced” set of chromosomes, meaning that each cell contains two copies of each chromosome for a total of 46 chromosomes per cell. A cellular state known as aneuploidy occurs when there is an imbalance in chromosome copy number, such that cells contain either additional or fewer chromosomes than the normal 46. Aneuploidy is a hallmark of cancer cells and is a common attribute of solid tumors. Despite its prevalence in cancer, the role of this chromosome copy number variation in tumor progression is not well understood. Due in part to its prevalence, it is hypothesized that aneuploidy plays a role in promoting tumor progression. This proposal seeks to test this hypothesis by constructing breast cancer cell lines that contain different copies of the chromosome arm 1q. We have chosen 1q because it is one of the most frequently seen chromosome copy number variations in breast cancer. We will remove extra copies of 1q in a breast cancer cell line that contains four copies of this chromosome using genetic techniques. Next, we will compare the ability of our derived cell lines, which have lost extra copies of 1q, to our parental cell lines, which have multiple copies of 1q, to form tumors in a series of assays in the laboratory and in animal models. We will also compare aneuploidy (multiple copies of 1q) and near-diploid (copies of 1q removed) cell lines for their sensitivities to various drug combinations that are designed to specifically inhibit aneuploid cells while leaving normal cells unharmed. Our work will address at least two of the overarching challenges identified by the Breast Cancer Research Program. These are to identify what drives breast cancer growth and determine how to stop it and to revolutionize treatment regimens by replacing them with ones that are more effective and less toxic. First, the experiments described above will help us understand whether aneuploidy plays a positive role in tumor progression. It is possible that we will identify chromosome 1q as being a major factor in allowing a cell to transition from a normal cell to a cancerous one. Furthermore, our findings may lead to an improved ability to stratify patient risk. If we know the significance and/or function of a very frequent characteristic of breast cancer, namely amplification of chromosome arm 1q, we may be able to identify patient risk based on the presence or absence of multiple copies of this chromosome. By identifying compounds that aneuploid cells are sensitive to but normal diploid cells are not, we can begin to identify new treatments with lower toxicity to breast cancer patients, which specifically target breast cancer cells but leave normal cells unharmed. My career goal is to become an independent investigator studying how aneuploidy affects breast cancer progression. For my PhD work, I received a strong foundation in using genetic and biochemical techniques while studying the regulation of cell identity, mating, and aspects of cell division in the human fungal pathogens Candida albicans and Candida lusitaniae. The experiments outlined in this proposal will allow me to successfully expand my research into the field of cancer biology. They provide the opportunity for me to establish crucial reagents to the study of aneuploidy, including the ability to selectively eliminate chromosomes from cancer genomes. There will also be many future directions that I can take this research in when I begin my own lab. For example, the causes underlying aneuploidy in breast cancer are not well understood, and this could be something I address in my own laboratory. Overall, the work outlined in this proposal takes an “aneuploidy-specific” approach to studying breast cancer and provides a platform on which I can establish myself as an independen
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810468
Entities
People
- Christine Scaduto
Organizations
- Cold Spring Harbor Laboratory
- United States Army