Examining the Role of Chromosomal Instability in Breast Cancer Evolution
Abstract
The diverse heterogeneity that exists among cells in any given tumor constitutes one of the most conspicuous features of triple-negative breast cancer. This heterogeneity allows cancer cells to constantly change and adapt to the environment. This capability is central to two of the deadliest properties of breast cancer: drug resistance and distant metastasis. The heterogeneity among cancer cells derives from genomic instability, where cells can rapidly change their genome or DNA content each time they divide. As such, they constantly acquire new properties that enable them to resist therapies and spread outside of the breast to distant organs. Genomic instability comes in two main forms. The first is point mutations, where cells introduce a single nucleotide base change, insertion, or deletion in their DNA as they divide. This form has been the subject of recent intense investigation. The second major form of instability is called numerical chromosomal instability, where cells occasionally alter the number of copies of each of the 23 human chromosomes each time they divide. Chromosomal instability exists in over 80% of human tumors and it is a distinctive hallmark of triple-negative breast cancer, which is known for its drug resistance and predilection to metastasize. As a result of this instability, it is common to find neighboring cancer cells that contain strikingly different chromosome complement. Unlike point mutations, the contribution of chromosomal instability to drug resistance and metastasis has been poorly understood. In this proposal, we aim to study how chromosomal instability influences drug resistance and metastasis. Our recent understanding of the mechanisms that lead to chromosomal instability in tumor cells has allowed us to experimentally dial up or dial down the frequency with which breast cancer cells can alter their chromosome numbers. In a way, it provides us with direct experimental control over how fast cells are able to change their genomic profile and therefore how rapidly they can adapt. We will capitalize on this newly acquired experimental ability to test whether suppressing chromosomal instability can suppress metastasis or delay drug resistance. We will perform these experiments in breast cancer cells lines and mouse models of triple-negative breast cancer. However, discoveries resulting from this work can be applied to other breast cancer types with elevated rates of chromosomal instability beyond the triple-negative subtype. By establishing a causal relationship between chromosomal instability and aggressive tumor behavior, our proposal aims to identify a novel cellular process that can be targeted in conjunction with existing therapies. Our rapidly growing understanding and appreciation of how cancer cells alter chromosome numbers will enable fast translation of these findings into the clinic. At the conclusion of the 3-year period during which the proposed work will be performed, we hope to initiate preclinical studies where we can investigate drugs that can alter chromosomal instability in conjunction with already established breast cancer treatment regimens with the purpose of delaying drug resistance and reducing the chances of distant metastases. If successful, we expect translation into humans to take place as early as 3 to 6 years from the end of this project funding period, as some of the drugs currently in development can influence the levels chromosomal instability, and this proposal would provide the rationale for their use in patients at high risk of metastasis or potentially drug-resistant tumors. There is no doubt that addressing two of the deadliest properties of breast cancer would extend patient survival and significantly improve outcomes. However, in order to attain this goal, rigorous experimental and mechanistic work is needed to understand the basis of tumor cell heterogeneity that enables the aggressive behavior of cancer. Our team, whose
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610315
Entities
People
- Samuel F Bakhoum
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army