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Breast Tumor Cell‐derived FGF‐5 Induces MEKK1‐dependent Chemokine Expression in Mammary Fibroblasts; Implications for Tumor Microenvironment
Author(s) -
Cuevas Bruce Daniel
Publication year - 2017
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.31.1_supplement.lb174
Subject(s) - cancer research , tumor microenvironment , biology , mammary tumor , microbiology and biotechnology , chemokine , tumor progression , immunology , cancer , breast cancer , inflammation , genetics , tumor cells
Breast tumors contain both transformed epithelial cells and non‐transformed stroma cells, and accumulating experimental evidence strongly suggests that this heterogeneous tumor microenvironment influences tumor growth and metastasis. Previously, we demonstrated that MAPK/ERK kinase kinase 1 (MEKK1) regulates gene expression in fibroblasts and breast tumor cells, and that transgene‐induced breast tumor metastasis is markedly inhibited in MEKK1‐deficient mice. In this work, we utilized expression array analysis of heterotypic cell cultures to determine the role of MEKK1 in stroma gene expression induced by breast tumor cells. We discovered that the breast tumor cell line MDA‐MB 231 constitutively expresses fibroblast growth factor 5 (FGF‐5), and that exposure to either tumor cell‐conditioned media or recombinant FGF‐5 induces chemokine expression in mammary fibroblasts. We demonstrate that FGF‐5‐induced expression of C‐C Motif Chemokine Ligand 5 (CCL5/RANTES) is markedly reduced in MEKK1‐deficient mammary fibroblasts, and that CCL5 expression requires MEKK1 kinase activity but is independent of MEKK1 ubiquitin ligase activity. Furthermore, we report that FGF‐5 initiates MEKK1 kinase activation and signaling in mammary fibroblasts. Finally, we show that breast tumor cell chemotaxis induced by fibroblasts is markedly inhibited by exposure to the CCL5 receptor antagonist Maraviroc, and that MEKK1‐deficient mammary fibroblasts are significantly less effective at promoting tumor cell chemotaxis than cells that express MEKK1. Overall, our findings suggest that MEKK1 is a key regulator of the stroma cell response to tumor cell‐derived FGF‐5. We conclude that MEKK1 is part of the signaling mechanism regulating a tumor/stroma paracrine loop that influences function of both transformed cells and stroma cells within breast tumors. Future studies in our lab will investigate the utility of the FGF‐5/CCL5 signaling axis as a set of targets that can be therapeutically inhibited to reduce tumor growth and progression. Support or Funding Information American Cancer Society, Illinois Div.