Integrin Regulation of Ferroptosis in Breast Cancer
Abstract
One of the major challenges in breast cancer research is to understand how tumor cells survive their journey from the primary tumor to a metastatic site. Surprisingly, these tumors are subjected to a multitude of harmful conditions that actually cause the death of many cells. Unfortunately, however, those cells that survive have acquired mechanisms that enable them to resist these harmful conditions, and these cells tend to be very aggressive. The death of tumor cells may seem like a simple process, but there are actually many different types of cell death that can occur in breast cancer. Understanding these processes and how some tumor cells evade them is important because this knowledge will allow the discovery of drugs that inhibit the survival of breast tumor cells and have the potential to reduce the morbidity and mortality associated with metastasis. We have become very interested in a novel type of cell death that is dependent on iron termed "ferroptosis." Almost nothing is known about this type of cell death in breast cancer (or any cancer). Our preliminary data, however, indicate breast tumor cells undergo this form of cell death unless they are protected by specific survival mechanisms. We also believe that these survival mechanisms are necessary for breast tumor cells to metastasize. The major goals of this proposal, therefore, are to understand the contribution of ferroptosis to breast cancer metastasis and to investigate the mechanisms used by breast tumor cells to evade this form of cell death. An important question is how this proposed research is relevant to breast cancer patients. We propose that these studies are particularly relevant to patients with more aggressive tumors such as triple-negative breast cancer. These tumors are so aggressive because they have acquired mechanisms to survive and metastasize. In fact, our proposed experiments will involve the use of tumor tissues from triple-negative patients, as well as a mouse model of triple-negative breast cancer. We believe from our initial results that these tumors express a protein on their surface that enables them to avoid iron-dependent cell death. Fortunately, there are experimental drugs available that inhibit this protein. Although this is a Level 1 Breakthrough Award, we are confident that the results we obtain will validate our hypothesis and provide justification for drug studies using our triple-negative mouse model initially. It is important to note that ferroptosis was discovered only 4 years ago and that there have been no relevant studies in breast cancer to date. We became excited about the role of ferroptosis in breast cancer and thought that the Breakthrough Award was an ideal mechanism for this project.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1710009
Entities
People
- Arthur M Mercurio
Organizations
- United States Army
- University of Massachusetts Medical School