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Tumor immune profiling and host NF-kappaB activity assessment in a novel Py230-based intraductal model for triple-negative breast cancer

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Abstract
[Introduction/Motivation:] In breast cancer research, the intraductal mouse model offers a valuable alternative for the classical fat pad inoculation route [1]. Understanding the tumor immunity and inflammation associated with the progression of intraductally inoculated triple-negative mammary tumors is key for immunotherapeutic target identification and treatment evaluation. [Methods:] Py230 mammary tumor cells, derived from a spontaneous tumor of MMTV-PYMT mice [2], were inoculated in the mammary ducts of lactating and syngeneic C57BL/6 mice that carry a luciferase reporter gene regulated by NF-kappaB [3], which has a major role in aggressive breast cancers [4]. In vivo imaging was used to monitor NF-kappaB-derived luminescence in the tumor-bearing mice. Proliferation of primary tumors and invasive breakthrough of the ductal epithelial barrier was determined through immunohistochemistry. Immune cell changes in the tumor microenvironment were also investigated immunohistochemically and confirmed by flow cytometry. Local cytokine profiles were investigated by multiplex assays and ELISA. [Results and Discussion:] Py230 cells grew exponentially and remained located in the mammary ducts, characteristic for the ductal carcinoma in situ (DCIS) stage, up to 3 weeks post-inoculation (p.i.). At 6 weeks p.i., tumor cells had invaded the mammary fat pad, characteristic for the invasive breast cancer stage. NF-kappaB-regulated luminescence increased exponentially over time in the tumor-bearing mice and was exclusively found in the primary tumor area and axillary lymph nodes. The progression from DCIS to invasive breast cancer was associated with an increase of innate (macrophages, neutrophils) and adaptive (CD4+ and CD8+ T-cells) tumor-associated immune cell populations. Whereas most of the selected cytokines decreased over time, the NF-kappaB-related cytokines TGF-β1 and BAFF [5, 6] increased exponentially in primary tumors. Overall, our study provides a profiling of breast tumor immunity and inflammation-associated NF-kappaB activity from early to late breast cancer stages, which is likely also of relevance for inflammatory breast cancer. References: [1] Steenbrugge J, Breyne K, Denies S, Dekimpe M, Demeyere K, De Wever O, et al. Comparison of the Adipose and Luminal Mammary Gland Compartment as Orthotopic Inoculation Sites in a 4T1-Based Immunocompetent Preclinical Model for Triple-Negative Breast Cancer. J Mammary Gland Biol Neoplasia. 2016;21(3-4):113-22. [2] Bao L, Cardiff RD, Steinbach P, Messer KS, Ellies LG. Multipotent luminal mammary cancer stem cells model tumor heterogeneity. Breast Cancer Res. 2015;17(1):137. [3] Carlsen H, Moskaug JO, Fromm SH, Blomhoff R. In vivo imaging of NF-kappa B activity. J Immunol. 2002;168(3):1441-6. [4] Van Laere SJ, Van der Auwera I, Van den Eynden GG, van Dam P, Van Marck EA, Vermeulen PB, et al. NF-kappaB activation in inflammatory breast cancer is associated with oestrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK hyperactivation. Br J Cancer. 2007;97(5):659-69. [5] Neil JR, Schiemann WP. Altered TAB1:I kappaB kinase interaction promotes transforming growth factor beta-mediated nuclear factor-kappaB activation during breast cancer progression. Cancer Res. 2008;68(5):1462-70. [6] Baud V, Karin M. Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov. 2009;8(1):33-40.

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Chicago
Steenbrugge, Jonas, Niels Vander Elst, Kristel Demeyere, Niek Sanders, Olivier De Wever, Steven Van Laere, and Evelyne Meyer. 2018. “Tumor Immune Profiling and Host NF-kappaB Activity Assessment in a Novel Py230-based Intraductal Model for Triple-negative Breast Cancer.” In Inflammatory Breast Cancer, 6th International Symposium, Abstracts.
APA
Steenbrugge, J., Vander Elst, N., Demeyere, K., Sanders, N., De Wever, O., Van Laere, S., & Meyer, E. (2018). Tumor immune profiling and host NF-kappaB activity assessment in a novel Py230-based intraductal model for triple-negative breast cancer. Inflammatory Breast Cancer, 6th International symposium, Abstracts. Presented at the 6th International Inflammatory Breast Cancer symposium: New concepts in the biology and management of aggressive breast cancers.
Vancouver
1.
Steenbrugge J, Vander Elst N, Demeyere K, Sanders N, De Wever O, Van Laere S, et al. Tumor immune profiling and host NF-kappaB activity assessment in a novel Py230-based intraductal model for triple-negative breast cancer. Inflammatory Breast Cancer, 6th International symposium, Abstracts. 2018.
MLA
Steenbrugge, Jonas et al. “Tumor Immune Profiling and Host NF-kappaB Activity Assessment in a Novel Py230-based Intraductal Model for Triple-negative Breast Cancer.” Inflammatory Breast Cancer, 6th International Symposium, Abstracts. 2018. Print.
@inproceedings{8586640,
  abstract     = {[Introduction/Motivation:] In breast cancer research, the intraductal mouse model offers a valuable alternative for the classical fat pad inoculation route [1]. Understanding the tumor immunity and inflammation associated with the progression of intraductally inoculated triple-negative mammary tumors is key for immunotherapeutic target identification and treatment evaluation.
[Methods:] Py230 mammary tumor cells, derived from a spontaneous tumor of MMTV-PYMT mice [2], were inoculated in the mammary ducts of lactating and syngeneic C57BL/6 mice that carry a luciferase reporter gene regulated by NF-kappaB [3], which has a major role in aggressive breast cancers [4]. In vivo imaging was used to monitor NF-kappaB-derived luminescence in the tumor-bearing mice. Proliferation of primary tumors and invasive breakthrough of the ductal epithelial barrier was determined through immunohistochemistry. Immune cell changes in the tumor microenvironment were also investigated immunohistochemically and confirmed by flow cytometry. Local cytokine profiles were investigated by multiplex assays and ELISA.
[Results and Discussion:] Py230 cells grew exponentially and remained located in the mammary ducts, characteristic for the ductal carcinoma in situ (DCIS) stage, up to 3 weeks post-inoculation (p.i.). At 6 weeks p.i., tumor cells had invaded the mammary fat pad, characteristic for the invasive breast cancer stage. NF-kappaB-regulated luminescence increased exponentially over time in the tumor-bearing mice and was exclusively found in the primary tumor area and axillary lymph nodes. The progression from DCIS to invasive breast cancer was associated with an increase of innate (macrophages, neutrophils) and adaptive (CD4+ and CD8+ T-cells) tumor-associated immune cell populations. Whereas most of the selected cytokines decreased over time, the NF-kappaB-related cytokines TGF-\ensuremath{\beta}1 and BAFF [5, 6] increased exponentially in primary tumors. Overall, our study provides a profiling of breast tumor immunity and inflammation-associated NF-kappaB activity from early to late breast cancer stages, which is likely also of relevance for inflammatory breast cancer.
References:
[1] Steenbrugge J, Breyne K, Denies S, Dekimpe M, Demeyere K, De Wever O, et al. Comparison of the Adipose and Luminal Mammary Gland Compartment as Orthotopic Inoculation Sites in a 4T1-Based Immunocompetent Preclinical Model for Triple-Negative Breast Cancer. J Mammary Gland Biol Neoplasia. 2016;21(3-4):113-22.
[2] Bao L, Cardiff RD, Steinbach P, Messer KS, Ellies LG. Multipotent luminal mammary cancer stem cells model tumor heterogeneity. Breast Cancer Res. 2015;17(1):137.
[3] Carlsen H, Moskaug JO, Fromm SH, Blomhoff R. In vivo imaging of NF-kappa B activity. J Immunol. 2002;168(3):1441-6.
[4] Van Laere SJ, Van der Auwera I, Van den Eynden GG, van Dam P, Van Marck EA, Vermeulen PB, et al. NF-kappaB activation in inflammatory breast cancer is associated with oestrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK hyperactivation. Br J Cancer. 2007;97(5):659-69.
[5] Neil JR, Schiemann WP. Altered TAB1:I kappaB kinase interaction promotes transforming growth factor beta-mediated nuclear factor-kappaB activation during breast cancer progression. Cancer Res. 2008;68(5):1462-70.
[6] Baud V, Karin M. Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov. 2009;8(1):33-40.},
  author       = {Steenbrugge, Jonas and Vander Elst, Niels and Demeyere, Kristel and Sanders, Niek and De Wever, Olivier and Van Laere, Steven and Meyer, Evelyne},
  booktitle    = {Inflammatory Breast Cancer, 6th International symposium, Abstracts},
  language     = {eng},
  location     = {Madrid, Spain},
  title        = {Tumor immune profiling and host NF-kappaB activity assessment in a novel Py230-based intraductal model for triple-negative breast cancer},
  url          = {http://www.ag-bc-madrid2018.com/},
  year         = {2018},
}