Syretta L. Tilghman, Ph.D.Associate Professor Pharmacology
LOCATION: Tallahassee, Dyson Room 224
PHONE: (850) 599-3933
PHONE: (850) 599-3933
BiosketchAlthough aromatase inhibitors, such as letrozole, are the standard endocrine therapy of choice for postmenopausal women with early-stage metastatic estrogen-dependent breast cancer, the major limitation in managing this disease is the development of drug resistance. Unfortunately, once resistance develops, the tumors display an epithelial to mesenchymal (EMT) phenotype, become estrogen independent, and are enriched for breast cancer stem cells (CSCs) thereby limiting favorable therapeutic outcomes. Our long-term goal is to better understand the mechanism(s) of aromatase inhibitor-resistant breast cancer, in order to contribute to both the improvement of current therapeutic modalities and the development of novel treatment strategies. The objective of our project is to determine the mechanism(s) by which glyceollin I reverses EMT and its impact on CSC formation and dissemination in letrozole-resistant breast cancer. We hypothesized that glyceollin I exhibits anti-metastatic behavior in letrozole-resistant breast cancer cells by targeting genes critical for EMT, metastasis and ultimately CSC formation. The rationale is that identification of the mechanism(s) of glyceollin I action and preliminary indications of its effectiveness in vivo will lay the groundwork for more in-depth analyses and development of effective treatment strategies for letrozole-resistant tumors and provide more general insight into approaches to develop new therapies for breast cancer cells that become resistant to established therapies. The first specific aim is to determine the mechanism(s) by which glyceollin I reverses EMT in letrozole-resistant breast cancer cells. We will accomplish this aim by testing the hypothesis that glyceollin I reverses EMT by targeting ZEB1 and reducing hypoxia. We will utilize the following approach: letrozole-resistant breast cancer cell lines will serve as a model system to measure the effects of glyceollin I treatment on cell morphology, EMT, motility and tumorigenesis in vitro and in vivo. The second aim is to identify the impact of glyceollin I treatment towards CSCs formation and dissemination in letrozole-resistant breast cancer. We hypothesize that that glyceollin I will inhibit the formation and dissemination of letrozole-resistant mammary CSCs by targeting EMT-related pathways and this will be accomplished using the following approach: a three-dimensional tissue cell culture model system will be utilized to study the impact of glyceollins on mammosphere formation, cell motility and CSC dissemination in vivo. This contribution is significant because it will be the first critical step in the series of studies leading to the development of novel phyto-antiestrogens used therapeutically in the treatment of letrozole refractory breast cancer. The proposed research is innovative, in our opinion, and a substantive departure from the status quo because disrupting the EMT process and prevention of CSC formation is a crucial pathway in restoring AI sensitivity of letrozole-resistant breast cancer, and glyceollin I, represents a novel anti-metastatic therapeutic that would be effective after initial hormone-receptor-based therapy has failed.