Factors That Regulate Breast Tumor Immunogenicity and Metastasis: Targeting Interferon Regulatory Factor 5 (IRF5)
Abstract
Metastasis of breast cancer cells from a primary tumor to distant sites is one of the main causes of breast cancer deaths. This process is driven by cooperation between tumors and their microenvironments, which include surrounding cells and soluble circulating blood factors. Primary tumors can educate secondary sites through the release of such factors that enable a back-and-forth communication between the sites. This communication allows the tumor to escape the immune system or be recognized by the immune system, and establishment of secondary sites for metastatic colonization. Exactly what the tumor-derived signals are and who regulates their generation is not known. Recent data in our lab suggests that a protein called interferon regulatory factor 5 (IRF5) is one such factor within a tumor that regulates the generation of soluble signals that can initiate or inhibit metastasis. IRF5 is a known mediator of the immune system, in part, through its ability to regulate the expression of soluble circulating factors, such as cytokines and chemokines. Later studies showed that IRF5 also regulates tumor growth. In breast cancer, IRF5 expression was found to be significantly decreased as a breast lesion progresses from non-malignant atypical ductal hyperplasia, to malignant ductal carcinoma in situ, and is eventually lost in about 80% of invasive ductal carcinomas. In an in vivo model of spontaneous mammary tumor metastasis, loss of IRF5 expression within a primary tumor resulted in enhanced lung metastases, while re-expression of IRF5 within the tumor significantly reduced metastasis. Additional studies showed that loss of IRF5 expression in the whole mouse (Irf5-/- Balb/c) leads to increased incidence of spontaneous mammary tumorigenesis as compared with normal mice (Irf5+/+ littermate controls). Together, these data suggest that loss of IRF5 expression is involved in the mechanisms that control both primary mammary tumor formation and metastasis. Based on these data, we hypothesize that IRF5 expression within a primary breast tumor defines its metastatic potential through direct (intrinsic) control of mammary epithelial cell migration, and indirect (extrinsic) control of the breast tumor-immune microenvironment and metastatic colonization. We propose that IRF5’s extrinsic control of tumor immunity and metastatic colonization is through the regulation of soluble tumor-derived factors. It is these aspects of IRF5 that will be studied in the current grant application. An in vivo model of spontaneous mammary tumor metastasis will be used to test whether outcomes from the mechanistic studies will lead to new therapeutic options for women with metastatic breast cancer. Thus, work proposed in the current grant application is directed toward a greater understanding of the mechanisms underlying metastatic breast cancer for the purpose of developing new, less toxic and more focused therapies for women with metastatic disease. The work will address three overarching challenges: (1) Identify why some breast cancers become metastatic, (2) distinguish deadly from non-deadly breast cancers, and (3) eliminate the mortality associated with metastatic breast cancer. The short-term impact of this study will be a significant advancement in our understanding of why some breast cancers metastasize and others do not. The long-term impact of this study will be the development of new therapeutic strategies that will lead to the prevention and/or eradication of metastatic disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910113
Entities
People
- Betsy J Barnes
Organizations
- The Feinstein Institute for Medical Research
- United States Army