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Natural history of tumor growth and immune modulation in common spontaneous murine mammary tumor models

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Abstract

Recent studies in patients with breast cancer suggest the immune microenvironment influences response to therapy. We aimed to evaluate the relationship between growth rates of tumors in common spontaneous mammary tumor models and immune biomarkers evaluated in the tumor and blood. TgMMTV-neu and C3(1)-Tag transgenic mice were followed longitudinally from birth, and MPA–DMBA-treated mice from the time of carcinogen administration, for the development of mammary tumors. Tumor-infiltrating CD4+ and CD8+ T-cells, FOXP3+ T-regulatory cells, and myeloid-derived suppressor cells were assessed by flow cytometry. Serum cytokines were evaluated in subsets of mice. Fine needle aspirates of tumors were collected and RNA was isolated to determine levels of immune and proliferation markers. Age of tumor onset and kinetics of tumor growth were significantly different among the models. Mammary tumors from TgMMTV-neu contained a lower CD8/CD4 ratio than that of other models (p < 0.05). MPA–DMBA-induced tumors contained a higher percentage of FOXP3+ CD4+ T-cells (p < 0.01) and MDSC (p < 0.001) compared with the other models. Individuals with significantly slower tumor growth demonstrated higher levels of Type I serum cytokines prior to the development of lesions compared to those with rapid tumor growth. Moreover, the tumors of animals with more rapid tumor growth demonstrated a significant increase in the expression of genes associated with Type II immunity than those with slower-progressing tumors. These data provide a foundation for the development of in vivo models to explore the relationship between endogenous immunity and response to standard therapies for breast cancer.

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Acknowledgments

The authors wish to thank the staff of the University of Washington Comparative Pathology Program/Histology and Imaging Core Research Laboratory especially Brian Johnson, Erin McCarty, and Cara Appel for their contributions to slide production as well as histochemical and immunohistochemical staining. This work was supported by the National Cancer Institute, U01 CA141539, the Department of Defense Grant, W81XWH-11-1-0760, and the National Cancer Institute contract, N01-CN-53300/WA#10. Mary L. Disis was supported by The Athena Distinguished Professorship for Breast Cancer Research.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

All experiments performed for this manuscript comply with the current laws of the country in which they were performed.

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Authors and Affiliations

  1. Tumor Vaccine Group, Center for Translational Medicine in Women’s Health, University of Washington, 850 Republican Street, 2nd Floor, Box 358050, Seattle, WA, 98109-8050, USA

    Ekram Gad, Lauren Rastetter, Meredith Slota, Marlese Koehnlein, Yushe Dang, Sasha Stanton & Mary L. Disis

  2. Department of Comparative Medicine, University of Washington, Seattle, WA, USA

    Piper M. Treuting

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  1. Ekram Gad
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  2. Lauren Rastetter
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Correspondence to Mary L. Disis.

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Ekram Gad and Lauren Rastetter have contributed equally to this work.

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Gad, E., Rastetter, L., Slota, M. et al. Natural history of tumor growth and immune modulation in common spontaneous murine mammary tumor models. Breast Cancer Res Treat 148, 501–510 (2014). https://doi.org/10.1007/s10549-014-3199-9

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  • DOI: https://doi.org/10.1007/s10549-014-3199-9

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