Abstract
Tumor necrosis factor alpha (TNF alpha) enhances proliferation of chemically-induced mammary tumors and of T47D human cell line through not fully understood pathways. Here, we explored the intracellular signaling pathways triggered by TNF alpha, the participation of TNF alpha receptor (TNFR) 1 and TNFR2 and the molecular mechanism leading to breast cancer growth. We demonstrate that TNFalpha induced proliferation of C4HD murine mammary tumor cells and of T47D cells through the activation of p42/p44 MAPK, JNK, PI3-K/Akt pathways and nuclear factor-kappa B (NF-kappa B) transcriptional activation. A TNF alpha-specific mutein selectively binding to TNFR1 induced p42/p44 MAPK, JNK, Akt activation, NF-kappa B transcriptional activation and cell proliferation, just like wild-type TNF alpha, while a mutein selective for TNFR2 induced only p42/p44 MAPK activation. Interestingly, blockage of TNFR1 or TNFR2 with specific antibodies was enough to impair TNF alpha signaling and biological effect. Moreover, in vivo TNF alpha administration supported C4HD tumor growth. We also demonstrated, for the first time, that injection of a selective inhibitor of NF-kappa B activity, Bay 11-7082, resulted in regression of TNF alpha-promoted tumor. Bay 11-7082 blocked TNF alpha capacity to induce cell proliferation and up-regulation of cyclin D1 and of Bcl-xLin vivo and in vitro. Our results reveal evidence for TNF alpha as a breast tumor promoter, and provide novel data for a future therapeutic approach using TNF alpha antagonists and NF-kappa B pharmacological inhibitors in established breast cancer treatment.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / drug effects
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Carcinogens
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Carcinoma, Ductal, Breast / chemically induced
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Carcinoma, Ductal, Breast / drug therapy
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Carcinoma, Ductal, Breast / physiopathology*
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Female
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Humans
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JNK Mitogen-Activated Protein Kinases / drug effects
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JNK Mitogen-Activated Protein Kinases / metabolism
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Mammary Neoplasms, Experimental / chemically induced
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Mammary Neoplasms, Experimental / drug therapy
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Mammary Neoplasms, Experimental / physiopathology*
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Medroxyprogesterone Acetate
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Mice
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Mice, Inbred BALB C
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Mitogen-Activated Protein Kinase 1 / drug effects
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / drug effects
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Mitogen-Activated Protein Kinase 3 / metabolism
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Neoplasms, Hormone-Dependent / chemically induced
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Neoplasms, Hormone-Dependent / drug therapy
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Neoplasms, Hormone-Dependent / physiopathology*
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Nitriles / pharmacology
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Proto-Oncogene Proteins c-akt / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Tumor Necrosis Factor, Type I / drug effects*
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Receptors, Tumor Necrosis Factor, Type I / immunology
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Signal Transduction / drug effects*
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Signal Transduction / immunology
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Sulfones / pharmacology
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Transcriptional Activation / drug effects
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Transcriptional Activation / immunology
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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3-(4-methylphenylsulfonyl)-2-propenenitrile
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Apoptosis Regulatory Proteins
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Carcinogens
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NF-kappa B
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Nitriles
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Receptors, Tumor Necrosis Factor, Type I
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Sulfones
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Tnfrsf1a protein, mouse
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Tumor Necrosis Factor-alpha
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Medroxyprogesterone Acetate
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Proto-Oncogene Proteins c-akt
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3