Prevention of Triple-Negative Breast Cancer by Natural Compounds
Abstract
Breast cancers are difficult to treat, especially if diagnosed at later stages. In the majority of breast cancers, the expression of three major proteins (estrogen receptor, progesterone receptor, and Her2) is responsible for tumor growth, and blocking the function of these proteins causes tumor cell death. However, an aggressive subtype of breast cancer, called triple-negative breast cancer, or TNBC, that lacks all three of these proteins is responsible for close to 30% of breast cancer-related deaths, according to Qiu and colleagues in their 2016 article in the Journal of Cancer. The standard of care for TNBC tumors involves platinum-based chemotherapies that act by causing DNA damage. However, around 40% of patients experience tumor recurrence despite aggressive therapy. At the University of Kansas Cancer Center, we work closely with one of our breast cancer survivors and patient advocate, Ms. Cheryl Jernigan. According to Ms. Jernigan, prevention of breast cancers, especially TNBC, would be best because of significant toxicities with current agents. Also, current prevention strategies focus on hormonally driven tumors. In order to develop a strategy to prevent TNBC recurrence and possibly primary prevention of tumors, we pursued studies on the mechanisms of DNA repair in TNBC cells. Normal cells use specific molecular machinery to repair damage to the DNA. This machinery is faulty in rapidly dividing cancer cells, which makes them sensitive to DNA-damaging drugs. Our group has studied the role of BRCA1, a protein that is critical for repairing DNA damage in cells extensively. Blocking the function of BRCA1 renders cells incapable of correcting DNA damage, and this results in the death of cancer cells, but not normal cells. This is because normal cells are not proliferating as quickly as cancer cells and have compensatory mechanisms to overcome the lack of BRCA1. Thus, BRCA1 is an attractive therapeutic target for TNBC cancer prevention. One DNA repair protein, which is involved in a particular type of DNA repair pathway, poly (ADP-ribose) polymerase (PARP), is currently being targeted by specific inhibitors as a way to hit DNA repair pathway defects. While this strategy has shown significant promise in cancer treatment, its utility in prevention has not been realized. In part, this is due to side effects of the oral agent, Olaparib, which include low blood counts, nausea, fatigue, and dizziness. Moreover, a potential risk associated with long-term PARP inhibition might be an increased mutation rate and cancer formation, particularly in those subjects that are BRCA mutation carriers. Recently, we have demonstrated that a protein called HSP90 is required for BRCA1 stability. Eliminating HSP90 greatly decreases BRCA1 levels in the cell. However, the current HSP90 inhibitor drugs show many side effects. Thus, there is an urgent need to develop HSP90 inhibitors that are effective and well tolerated. We have found that the natural compounds celastrol and gedunin stop HSP90 function without the bad side effects on normal cells. Therefore, natural compounds for cancer prevention and treatment might be a better way. Our preliminary data suggest that celastrol and gedunin increase HSP90-BRCA1 interaction and keep BRCA1 in the cytoplasm (away from the DNA). This led us to the hypothesis that celastrol and gedunin inhibit DNA damage repair. We further hypothesize that oral administration of celastrol and gedunin will inhibit TNBC progression. We will test this hypothesis in three specific aims. In Aim 1, we will demonstrate that celastrol and gedunin enhance HSP90:BRCA1 interaction and impair BRCA1-mediated homologous recombination and DNA repair in vitro. In Aim 2, we will characterize the toxicity profile of the agents and determine the bioavailability, pharmacokinetic, and pharmacodynamics properties in order to develop these agents for clinical trials. Finally, in Aim 3, we will perform proof-of-pr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810031
Entities
People
- Shrikant Anant
Organizations
- United States Army
- University of Kansas Medical Center