LGR4 in Breast Cancer Progression and Therapy
Abstract
This proposal addresses the overarching challenge of identifying the drivers of breast cancer growth and determining how to stop it. In particular, it aims to characterize and validate a novel target for the treatment of triple-negative breast cancer in preclinical models. Triple-negative breast cancer is a subtype of breast cancer with the worst survival outcome due to the lack of targeted therapy and frequent development of resistance to chemotherapy, which is non-specific for malignant cells. A major driver of chemoresistance is the existence of cancer stem cells, which are a small population of cells in a tumor that are better able than other tumor cells to survive chemotherapy and re-grow tumors after therapy. Therefore, therapeutic agents that can target cancer stem cells have the potential of preventing relapse. Macrophages are a type of immune cells that can act to trigger inflammation or to suppress an immune response. Macrophages located in tumors are tricked by tumor cells into adopting a behavior that promotes tumor growth and metastasis. Specific targeting of tumor-associated macrophages and switching them to launch an anti-tumor response can unleash the body s own immune system to potentially destroy the tumor. LGR4 is a protein present on the cell surface of both breast cancer cells and tumor-associated macrophages. Mice lacking LGR4 have delayed breast cancer occurrence and many fewer cancer stem cells than mice with LGR4, suggesting that LGR4 is crucial for cancer stem cell maintenance. Macrophages of LGR4-deficient mice have increased functions related to tumor-killing capacity. A high level of LGR4 in breast tumors is associated with decreased patient survival. This proposal will test the hypothesis that LGR4 is a key protein in both breast cancer stem cells and tumor-associated macrophages in triple-negative breast cancer. We will perform a series of experiments on cultured human breast cancer cells and mouse models to determine the roles of LGR4 in the survival of cancer stem cells. Furthermore, we will test whether loss of LGR4 in tumor-associated macrophages shifts them from an immune suppressive state to an inflammatory state and whether this affects triple-negative breast cancer growth and metastasis. Importantly, as we have preliminarily established two novel approaches for targeting LGR4-producing macrophages and tumor cells, we will evaluate whether these two new targeted therapeutics can inhibit the growth of breast cancer cells in mouse models. Finally, we will test whether these drugs can improve the efficacy of two chemotherapies that are commonly prescribed to treat triple-negative breast cancer. Successful completion of our studies would identify and validate LGR4 as a key driver of both cancer stem cells and macrophages affecting the growth, metastasis, and immune evasion of triple-negative breast cancer. Furthermore, our project will include preclinical testing of two novel therapeutics targeting LGR4 in triple-negative breast cancer models. This will pave the way for a rapid transition to clinical testing in triple-negative breast cancer patients, who currently have no targeted therapies available.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710087
Entities
People
- Qingyun Liu
Organizations
- United States Army
- University of Texas Health Science Center at Houston