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Chemopreventative activity of a cyclooxygenase‐2 inhibitor in FBV transgenic mice with a CMV promoter driven MMTV/neu transgene
Author(s) -
Abe Fuminori,
Donkor Moses,
Scholar Eric,
Dafferner Alicia,
Westphal Sherry,
Hoke Traci,
Talmadge James E.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1076.18
Subject(s) - spleen , immune system , celecoxib , mammary tumor , myeloid derived suppressor cell , oncogene , genetically modified mouse , cancer research , transgene , mouse mammary tumor virus , biology , microbiology and biotechnology , immunology , cancer , cell cycle , medicine , virus , pharmacology , breast cancer , suppressor , biochemistry , gene
We have previously examined the effect of transplantable, murine mammary tumor growth on the expansion of myeloid‐derived suppressor cells (MDSCs) and their tumor infiltration, as well as the relationship of MDSC frequency to T cells. We report an extension of these studies using mouse mammary tumor virus (MMTV) promoter driven HER2/Neu proto‐oncogene transgenic, FBV mice (neu transgenic mice). Studies in this model also included an assessment of the tumor chemopreventative activity by the cyclooxygenase‐2 inhibitor, celecoxib (80 mg/kg in drinking water). We report that celecoxib administration delayed tumor induction, increased the incidence of apoptotic tumor cells in the treated mice, and prolonged survival. In addition, immune surrogates in the spleens and tumors were studied by flow cytometry and quantitative reverse transcriptase polymerase chain reaction analysis. These studies revealed that tumor development expanded MDSCs numbers and depressed the T cell frequency in the spleen. Celecoxib administration reduced the MDSC expansion and T cell depression in the spleen and tumors. The tumor associated increase in transcript levels of COX‐2, G‐CSF, GM‐CSF TGF‐β, NOS‐2, ARG‐1 and VEGF‐α were reduced by celecoxib administration. The greatest increase in cytokine and enzyme levels were observed within tumor infiltrating leukocytes relative to spleen cells, suggesting a tumor‐immune cell interaction. Supported in part by funding from NIH grant 5 RO1 AT001739, Eppley Cancer Center and Nebraska DHHS LB506.