Cell-Killing Effect of Orphan Receptor TR3 in Breast Cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Vitamin A compounds, collectively called retinoids, show promise as anti-cancer agents for breast cancer prevention and treatment. However, clinical effects of classical retinoids are limited to hormone-dependent breast cancer. Recent studies have indicated that a retinoid derivative, called AHPN, is a promising agent against both hormone-dependent and independent breast cancer by causing their death (apoptosis). Dr. Xiao-kun Zhang's lab at the Burnham Institute recently discovered that the death-inducing effect of AHPN is mediated by a protein called TR3. TR3 was conventionally considered to function in the nucleus as a factor that controls expression of genes. Dr. Zhang's lab found that TR3 migrates from the nucleus to an intracellular organelle called mitochondria to exert killing activity; however, how TR3 migration is controlled is not known, and it is very important to know this in order to develop agents to induce TR3 killing activity to destroy breast cancer cells.
 
 
 
 
 
 
 
 Previously several laboratories showed that TR3 can interact with another protein called RXR. Dr. Zhang's lab recently found that RXR and its regulators (a class of specific retinoids) may play a role in the control of TR3 migration and breast cancer killing activity. However, it is very difficult to show whether TR3 activity is regulated by RXR or by some other factors in breast cancer cells due to the complexity of human cells. Fortunately, scientists have found a much simpler system, the fruit fly Drosophila melanogaster, to study function and regulation of human proteins.
 
 
 
 
 
 
 
 We propose to take a genetic approach to examine the interactions between TR3, RXR, and other components of the cell death pathways by using the fruit fly as a model. We hypothesize that the mechanism of TR3 control and killing activities are very similar in flies and in humans.
 
 
 
 
 
 
 
 We plan to use the fruit fly to identify modulators of TR3 killing activity, including fly RXR. Drosophila melanogaster is a good model to use because genetic modification is relatively easy. Certain genes can be either "knocked out" or inserted, resulting in an altered fly genotype that is reflected by changes in visible characteristics and behaviors (phenotypes). Molecular cloning techniques will be used to make these genotypes, and histology techniques will be used to study the phenotype of each of the experimental genotype fly lines. The regulators identified in the fly will be further studied in human breast cancer cells.
 
 
 
 
 
 
 
 Because RXR and TR3 compounds possess anti-cancer properties in breast cancer cells irrespective of hormone status, it is envisaged that these agents may be effective chemotherapeutic agents for breast cancer treatment. However, in order to identify a new generation of such compounds, it is essential to understand their mechanism of action. Our previous discovery that transcriptional factor TR3 migrates from the nucleus to mitochondria to induce killing activity is exciting. Our hypothesis that TR3 killing activities is regulated by RXR and its ligands is novel, and the proposed study of using fly system is also novel in nature.