Targeting Histone Modifications to Promote LIFR and Tumor Dormancy
Abstract
Breast cancer cells frequently spread to other organs in the body and are especially likely to spread to the bone marrow and lungs. These cancer cells can take up prolonged residence in these organs and can remain there even once a patient is considered in remission. Tumor cells that reside in distant organs long-term but are not detectable by clinical imaging services are termed dormant, or non-proliferating, tumor cells. We now know that these cells eventually lead to breast cancer patient recurrence. However, it is unclear exactly which signals inside and outside of the cell cause these dormant tumor cells to wake up and lead to recurrence. This research will therefore address the overarching challenge to determine why/how breast cancer cells lie dormant for years and then re-emerge, and determine how to prevent recurrence. When cancer cells spread to other parts of the body, we know that they encounter different oxygen levels in different organs. For example, they encounter high oxygen levels in the lungs and low oxygen levels (termed hypoxia) in the bone. Our lab previously reported that a protein called the leukemia inhibitory factor receptor (LIFR) keeps breast cancer cells in a dormant state, and if LIFR is lost or reduced, this allows tumor cells to proliferate and take over the bone marrow, causing bone destruction and a poor outcome for patients. We proposed that low oxygen levels in the bone cause this reduction in LIFR. We also found that a Food and Drug Administration (FDA)-approved drug called valproic acid stimulates LIFR. Valproic acid inhibits histone deacetylases (HDACs), but we do not know exactly how it works to stimulate LIFR expression in breast cancer cells. Importantly, valproic acid is able to enhance LIFR when breast cancer cells are grown in both high oxygen levels (such as the oxygen levels cancer cells encounter in the lungs) and when breast cancer cells are grown in hypoxia (such as the oxygen levels cancer cells encounter in the bone marrow). We hypothesize that LIFR is regulated by HDACs in breast cancer cells both in high oxygen levels and in hypoxia. The proposed project aims to determine whether we can use HDAC inhibitors to stimulate LIFR expression on breast cancer cells, which may keep the cancer cells in a chronic dormant state and prevent their recurrence. There are five HDAC inhibitors that are FDA-approved or in clinical trials for other diseases and non-breast tumor types, and we will test all of these inhibitors in breast cancer cells to determine how they regulate LIFR and other genes that we know can promote cancer cell dormancy. These studies will also identify which inhibitor works best at keeping tumor cells dormant in mice. These studies have the potential to benefit breast cancer patients currently in remission, but it may also be beneficial for breast cancer patients who have aggressive disease. We will test the HDAC inhibitors on several different types of breast cancer cell lines, including dormant and aggressive breast cancer cell lines. If our hypothesis is correct, these HDAC inhibitors may be quickly applied to breast cancer patients in remission to prevent recurrence, since they are already FDA-approved. Thus, the time to establish a patient-related outcome is relatively quick, since these studies would provide appropriate data to initiate a future clinical trial. Due to the nature of dormancy and recurrence, the benefit would be long-term since we would give these drugs to breast cancer patients in remission and monitor for signs of recurrence over many years. Some patients have reported negative side effects from HDAC inhibitors, including gastrointestinal distress and liver toxicity, so we will use low doses in our mouse studies to be certain we can stimulate LIFR and promote dormancy without exacerbating toxicity. Ideally, we wish to eradicate breast cancer cells altogether, but we reason that it will be impossible to know if all tumor c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810029
Entities
People
- Rachelle Johnson
Organizations
- United States Army
- Vanderbilt University