Targeting Breast Tumor Stem Cells with Cell Cycle Inhibitors
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: The main cause of death from breast cancer is the recurrence of metastatic disease, which can occur years after treatment of the initial breast tumor. We are investigating methods to prevent tumor recurrence that can be used in combination with conventional chemotherapeutics. Breast cancer recurrence has been blamed on a small population of cells within a breast tumor that are distinct from the bulk of the tumor. These cells are thought to be resistant to current chemotherapies, and are able to remain dormant for years until unknown signals can trigger them to divide. Further characterization of these cells has shown that these cells exhibit typical stem cell properties such as the ability to self-renew and give rise to many different types of cells. Our goal is to specifically eliminate these stem cell-like cells. Our approach is to use a class of small molecule drugs known as CDK (cycle-dependent kinase) inhibitors that we have previously shown to be effective at killing embryonic stem cells. We will determine the effect of CDK inhibitors on breast cancer stem cells. Additionally we will investigate the molecular mechanism by which CDK inhibitors can induce cell death in order to learn more about the biology of the breast cancer stem cells.
 
 
 
 
 
 
 
 Previous research has shown that cells expressing high levels of a protein called Myc are more sensitive to CDK inhibitors. Both embryonic stem cells and stem cell-like cancer cells express high levels of Myc. Our first aim is to determine whether CDK inhibitors can specifically kill breast cancer stem cells, and what role Myc has in any observed cell death. Additionally, we will investigate whether CDK inhibitors affect the breast cancer cell’s capability to form tumors in mice, which has previously been attributed to the presence of breast cancer stem cells. Finally we will ask how CDK inhibitors can kill stem cells. CDK inhibitors are known to affect multiple cellular proteins that are important for cell division and growth. We will determine which individual proteins trigger cell death when inhibited.
 
 
 
 
 
 
 
 For these studies will examine the effect of CDK inhibitors on a collection of breast cancer cell lines that have been established from human breast tumors. We will specifically look at small populations of breast cancer stem cells within the cells lines, which can be identified by the expression of unique cell surface proteins. Additionally, we will use an established technique known as RNA interference (RNAi) to deplete Myc levels in our breast cancer cell lines. These approaches will test our hypothesis that CDK inhibitors can kill the breast cancer stem cells in a Myc-dependent manner, and therefore decrease the tumor forming capability of these cell lines.
 
 
 
 
 
 
 
 This project explores a novel mechanism to selectively kill breast cancer stem cells as a new approach to treatment. This could be used to prevent recurrence of metastatic disease and treat poorly differentiated cancers, such as triple negative breast cancers.