Exploiting Epigenetic Vulnerabilities in Breast Cancers with Chromosomal Instability
Abstract
The heterogeneity that exists among cells in any given tumor constitutes one of the most conspicuous features of aggressive breast cancers. This diversity 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. This heterogeneity 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. One major form of genomic instability is called chromosomal instability, where cells make mistakes each time they divide their chromosomes, and this leads to unequal distribution of chromosomes. Chromosomal instability exists in over 80% of human tumors, and it is a distinctive hallmark of triple-negative breast cancer as well as a considerable subset of estrogen receptor-positive and Her2-positive breast cancers. Breast tumors with chromosomal instability have a much higher chance to spread to distant organs and relapse after therapy. It has been assumed that the way chromosomal instability generates cell-to-cell variability is through shuffling of the genetic material. When cells in the same tumor have a diverse number of copies of the same genetic material, they can make different amounts of RNA and protein, thus leading to heterogeneity. We made the interesting observation that in addition to changing the genetic content, chromosomal instability can also lead to alteration in the epigenetic context in breast cancer cells. The same genetic material can be read or interpreted differently by each cell. Changes in this epigenetic state promote yet an additional layer of heterogeneity that facilitates breast cancer cell adaptation. In this proposal, we hope to better understand how epigenetic abnormalities arising from chromosomal instability impact the level of cancer promoting genes in breast cancer. We also aim to test whether these changes can also lead to additional structural changes in the chromosome. Finally, we will test whether preventing some of these epigenetic changes can be used to suppress breast cancer metastasis. Our goal is to deepen our understanding of the key processes by which chromosomal instability shapes breast cancer cell behavior and use this knowledge to intervene and prevent breast cancer progression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310199
Entities
People
- Samuel F Bakhoum
Organizations
- Sloan-Kettering Institute
- United States Army