Targeting APE1 Interaction with DNA G-Quadruplex to Prevent Metastasis in Triple-Negative Breast Cancer
Abstract
Cancer remains one of the leading cause of deaths among Americans. Breast cancer is the second leading cause of cancer-related deaths in women. According to American Cancer Society, about 287,850 women will be diagnosed of invasive breast cancer in year 2022. An estimated 43,250 breast cancer deaths in women are expected in year 2022. Although over past decade we have made significant advancement in early diagnosis and targeted therapy for majority of breast cancer patients, about 10% to 20% of breast cancers that are called triple-negative breast cancer (TNBC) do not respond to conventional hormonal or antibody therapies due to lack of estrogen receptors, progesterone receptors, and ErbB2 overexpression. This subtype of breast cancer has a tendency to grow fast and spread (metastasize) more quickly to lungs and brain than other subtypes of breast cancer. TNBC is frequently observed in younger women and threaten patients’ median overall survival to 9-13 months due to its high rate of metastasis and recurrence. Standard chemotherapy and radiation do not work effectively, and metastasis is responsible for greater than 80% of death of women with TNBC. Therefore, we need more research to identify and characterize the factors that drive metastasis to allow the development of new therapeutic agents to inhibit TNBC metastasis. Overarching Challenges: Our research will address the following overarching challenges: Identify why some breast cancers become metastatic and Eliminate the mortality associated with metastatic breast cancer by elucidating the mechanisms by which TNBC cells drive distant metastasis and by identifying novel therapeutic targets to prevent metastasis. We have identified AP-endonuclease (APE1), a protein that repairs DNA damages and controls gene expression, is elevated in TNBC, and patient with a high level of APE1 in tumors cells had a shorter survival due to fast spreading of tumors from primary site (breast) to lungs, bone, and brain. To begin to understand how overexpression of this protein promotes TNBC metastasis, we discovered a novel pathway, the subject of this proposal. APE1 protein binds to a four-stranded DNA structures known as quadruplexes (G4) present in gene promoters and facilitates expression of a set of genes that drive migrations of tumor cells from primary site (breast) to distant organs. DNA is usually depicted as double-stranded, but recent research shows that parts of the genome that adopt four-stranded structures known as G4 control expression of a set of proteins needed for migration of tumor cells and their colonization/growth in other organs. APE1 binds to this special G4 DNA structure to alter the expression of genes. If tumor cells do not have APE1 protein, then they fail to migrate. In this proposal, we are interested in learning more about how these elevated G4-DNA structures and APE1 drive tumor cells migration and metastatic progression, and if we can find a way to disrupt APE1’s function in binding with G4 DNA, we might be able to modulate gene expression in tumor cells and stop their migration and invasion. Significantly, a small molecule, called TMPyP4, can bind to G4 DNA and block APE1 binding to G4, which has a significant effect on gene expression and affects cell migration. We predict that this small molecule can inhibit tumor cells migration and colonization to lungs and brain and prevent metastasis. To test this idea, we will generate TNBC in mice and examine whether treatment with TMPyP4 can inhibit tumor spreading to lungs. If successful, this will represent a novel therapeutic strategy to prevent metastasis in TNBC patients. Successful completion of this project will establish that elevated levels of APE1 and G4 DNA promote metastasis-related genes expression in TNBC, and small molecule TMPyP4 (G4 ligand) can be used to prevent TNBC metastasis and improve patients’ outcomes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310052
Entities
People
- Vimla Band
Organizations
- United States Army
- University of Nebraska Medical Center