Targeting the Tumor Microenvironment and Metastatic Niche in Breast Cancer
Abstract
Breast cancer cells produce growth factors and cytokines that modulate the behavior of other cell types in their environment, which allows tumors to grow and metastasize. In this proposal, we will examine how breast cancer cells produce these cytokines to modulate their environment and explore ways to inhibit their production. Thus, this proposal will address the overarching challenges of (1) identifying what drives breast cancer growth and determining how to stop it; (2) identifying why some breast cancers become metastatic; and (3) revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. Our published and preliminary data indicate that the Neuroepithelial transforming gene 1 (Net1) is an important regulator of breast cancer tumorigenesis and metastasis that potently regulates cytokine production in breast cancer cells. The Net1 gene is preferentially amplified in metastatic breast cancer patients, and we have shown that patients who exhibited high Net1 activity had worse overall survival. Moreover, we have found that deletion of the Net1 gene in mice slows mammary gland tumorigenesis and dramatically inhibits lung metastasis. Importantly, Net1 deletion also inhibited the expression of cytokines that normally control innate immune cell recruitment to tumors. These immune cells can potently stimulate tumor growth and prevent attack by the rest of the immune system. Previous attempts to inhibit the ability of breast cancer cells to secrete cytokines that alter immune system behavior have focused on the actions of individual cytokines and have involved treatments that would block the function of these cytokines throughout the body, thus causing many unwanted side effects. Our work indicates that Net1 functions as a nexus to control the expression of a wide range of immune modifying cytokines by breast cancer cells. Thus, inhibition of Net1 function offers the possibility of blocking many cytokines at once in a specific way, since Net1 is highly overexpressed in the breast tumors relative to normal tissues. In this proposal, we will demonstrate that Net1 overexpression correlates with cytokine expression in human breast cancer patients, and prove that Net1 deletion or blockade with Net1 inhibitors that we have discovered will sensitize breast tumors to the chemotherapeutic doxorubicin or to a targeted immune checkpoint therapy. This work will be impactful because it may offer a way to improve outcomes in patients treated with standard chemotherapies, which often do not fully eradicate disease. This work may also demonstrate a way to enable immune checkpoint inhibitors to work in breast cancer, which have been miraculous in other types of cancer but have not yet been helpful in breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010004
Entities
People
- Jeffrey A Frost
Organizations
- United States Army
- University of Texas Health Science Center at Houston