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TNF alpha acting on TNFR1 promotes breast cancer growth via p42/P44 MAPK, JNK, Akt and NF-kappa B-dependent pathways.
Exp Cell Res. 2008 Feb 01; 314(3):509-29.EC

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.

Authors+Show Affiliations

Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Buenos Aires, C1428ADN, Argentina.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18061162

Citation

Rivas, Martín A., et al. "TNF Alpha Acting On TNFR1 Promotes Breast Cancer Growth Via p42/P44 MAPK, JNK, Akt and NF-kappa B-dependent Pathways." Experimental Cell Research, vol. 314, no. 3, 2008, pp. 509-29.
Rivas MA, Carnevale RP, Proietti CJ, et al. TNF alpha acting on TNFR1 promotes breast cancer growth via p42/P44 MAPK, JNK, Akt and NF-kappa B-dependent pathways. Exp Cell Res. 2008;314(3):509-29.
Rivas, M. A., Carnevale, R. P., Proietti, C. J., Rosemblit, C., Beguelin, W., Salatino, M., Charreau, E. H., Frahm, I., Sapia, S., Brouckaert, P., Elizalde, P. V., & Schillaci, R. (2008). TNF alpha acting on TNFR1 promotes breast cancer growth via p42/P44 MAPK, JNK, Akt and NF-kappa B-dependent pathways. Experimental Cell Research, 314(3), 509-29.
Rivas MA, et al. TNF Alpha Acting On TNFR1 Promotes Breast Cancer Growth Via p42/P44 MAPK, JNK, Akt and NF-kappa B-dependent Pathways. Exp Cell Res. 2008 Feb 1;314(3):509-29. PubMed PMID: 18061162.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TNF alpha acting on TNFR1 promotes breast cancer growth via p42/P44 MAPK, JNK, Akt and NF-kappa B-dependent pathways. AU - Rivas,Martín A, AU - Carnevale,Romina P, AU - Proietti,Cecilia J, AU - Rosemblit,Cinthia, AU - Beguelin,Wendy, AU - Salatino,Mariana, AU - Charreau,Eduardo H, AU - Frahm,Isabel, AU - Sapia,Sandra, AU - Brouckaert,Peter, AU - Elizalde,Patricia V, AU - Schillaci,Roxana, Y1 - 2007/10/13/ PY - 2007/05/11/received PY - 2007/10/08/revised PY - 2007/10/10/accepted PY - 2007/12/7/pubmed PY - 2008/4/15/medline PY - 2007/12/7/entrez SP - 509 EP - 29 JF - Experimental cell research JO - Exp Cell Res VL - 314 IS - 3 N2 - 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. SN - 0014-4827 UR - https://www.unboundmedicine.com/medline/citation/18061162/TNF_alpha_acting_on_TNFR1_promotes_breast_cancer_growth_via_p42/P44_MAPK_JNK_Akt_and_NF_kappa_B_dependent_pathways_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4827(07)00474-0 DB - PRIME DP - Unbound Medicine ER -