Immune cell infiltration is commonly observed in breast carcinomas and the composition of immune cells associated with breast tumors can predict both therapeutic response and survival outcome. However, the specific immune cell compositions associated with the earliest stages of tumor initiation have not been extensively evaluated. Studies have suggested that the immune cells associated with a tumor vary greatly depending on tumor stage. Therefore, understanding how the immune response changes as tumors form and progress, as well as determining the specific mechanisms through which the changing immune response contributes to the each stage will lead to more effective methods of targeting the immune response. Using an inducible model of fibroblast growth factor receptor 1 (FGFR1) activation, we have characterized the initial responses of the immune system to oncogenic activation in mammary epithelial cells. Upon oncogenic initiation, epithelial cells rapidly produce inflammatory cytokines that signal to both recruit and activate macrophages, which contribute to the generation of an immunosuppressive environment. We propose that the MMTV-iFGFR1 transgenic mouse model can be used to study the changes in the immune response during the transition from initial oncogenic alterations in mammary epithelial cells to the formation of locally invasive lesions. Based on our preliminary studies, we hypothesize that in response to oncogenic initiation, epithelial cells produce cytokines that act directly on macrophages to induce an immunosuppressive phenotype during the earliest stages of malignant transformation. Proposed studies will 1) characterize the effects of oncogenic epithelial initiation on the immune response, 2) determine the contribution of epithelial cell-derived cytokines to early stage tumorigenesis, and 3) identify gene profiles in macrophages associated with different stages of epithelial lesions. The studies outlined in this proposal will provide a strong foundation with which to further assess immune responses to other initiating oncogenes during tumor initiation and the specific contributions of epithelial cells and macrophages to the immune response during the earliest stages of malignant transformation. Ultimately, obtaining a better understanding of mechanisms that regulate immune cell function will ultimately lead to the identification of markers that prediction of immune response and the development of potential therapeutic approaches for patients with the earliest stages of preneoplastic lesions.

Public Health Relevance

The proposed studies focus on identifying the mechanisms that regulate the immune responses to initiated epithelial cells. The proposed research is relevant to human health because understanding the mechanisms underlying the immune responses to the earliest stages of malignant transformation of breast cancer and other cancers will ultimately lead to the development of novel biomarkers that predict response as well as therapeutic strategies for early stage breast cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-SRLB-U (J1))
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Howcroft, Thomas K
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University of Minnesota Twin Cities
Schools of Medicine
United States
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Brady, Nicholas J; Farrar, Michael A; Schwertfeger, Kathryn L (2017) STAT5 deletion in macrophages alters ductal elongation and branching during mammary gland development. Dev Biol 428:232-244
Bohrer, Laura R; Chaffee, Thomas S; Chuntova, Pavlina et al. (2016) ADAM17 in tumor associated leukocytes regulates inflammatory mediators and promotes mammary tumor formation. Genes Cancer 7:240-253