Viral Infection as a Secondary Driver of Aggressive Breast Cancer Growth and Metastasis
Abstract
Can we identify why some breast cancers become life-threatening metastasis? This question has remained at the top of the list for many clinicians, researchers, and patients. Metastasis of cancer cells from the breast to distal target organs is the single-most important cause of mortality in women with breast cancer. One of the most challenging aspects of eradicating breast cancer and increasing the survival rates of women with breast cancer is the prevention and/or treatment of metastasis. Arguably, breast cancers that do not metastasize become a far more manageable form of the disease. Recent next-generation sequencing studies have confirmed that TP53 mutations are the most frequent alterations in breast carcinomas, occurring in all subtypes of human breast cancer at varying rates. Moreover, TP53 mutation can enhance metastasis in basal-like tumors, providing evidence that the p53 tumor suppressor protein acts in part to prevent metastasis. However, loss of p53 alone in the mammary gland is often not sufficient for robust metastasis, suggesting that other regulatory mechanism act in concert with TP53 mutation to stimulate metastasis. Identifying these key regulatory pathways is paramount to preventing life-threatening metastasis in breast cancer. Our exciting new combined published and preliminary findings indicate that the activation of a common anti-viral signaling pathway is sufficient to drive enhance tumorigenesis and metastasis of breast cancer cells. This has led us to re-think the process of metastasis, now allowing for an extrinsic viral component. Could it be that aggressive metastasis is the result of TP53 mutations and viral infection? That is, latent breast tumor cells are triggered to metastasize by an otherwise innocuous virus. We hypothesize that a common anti-viral regulatory pathway provides p53-mutant mammary tumor cells with a tremendous advantage in vivo and therefore serves as a driver for growth and metastasis. To test this hypothesis, we propose to de-construct this pathway in highly metastatic cells that harbor TP53 mutations and exhibit an activation of this pathway. Furthermore, we will determine whether we can trigger metastasis in TP53 mutant cells through the activation of this anti-viral pathway. Our experiments will cover both in vitro and in vivo aspects of growth, invasion, and metastasis using established human breast cancer cells, primary mouse mammary epithelial cells, and patient-derived tumor xenografts. Our combined expertise in tumor suppressors and oncogenes along with our unlimited access to the Human-in-Mouse Xenograft Core at Washington University gives us tremendous leverage in successfully obtaining large amounts of patient tumors to perform our in vivo analysis. We have recruited key collaborators to insure that we perform high-risk, yet sound experiments that are the most relevant to current breast cancer patients. Identification of required signaling components in aggressive TP53 mutant breast cancers will lead to the discovery of novel drugs targeting the key genes and genetic pathways responsible for breast cancer metastasis. How fast can we get there? The identification of anti-viral pathways suggests that preventable viral infections are a targetable outcome as well as the RIG-I signaling pathway.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510388
Entities
People
- Jason D Weber
Organizations
- United States Army
- Washington University in St. Louis