TNF[alpha] acting on TNFR1 promotes breast cancer growth via p42/P44 MAPK, JNK, Akt and NF-[kappa]B-dependent pathways

• Published in: Experimental cell research 2008-02, Vol.314 (3), p.509
• Main Authors: Rivas, Martín A, Carnevale, Romina P, Proietti, Cecilia J, Rosemblit, Cinthia, Beguelin, Wendy, Salatino, Mariana, Charreau, Eduardo H, Frahm, Isabel, Sapia, Sandra, Brouckaert, Peter, Elizalde, Patricia V, Schillaci, Roxana
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ANTIBODIES; Binding sites; BORON CHLORIDES; Breast cancer; CARCINOMAS; CELL PROLIFERATION; Cellular biology; GROWTH; IN VITRO; IN VIVO; MAMMARY GLANDS; RECEPTORS; Signal transduction; TUMOR CELLS; TUMOR PROMOTERS; Tumors
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2007.10.005

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 TNF[alpha] 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-kappaB (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-xL in 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 ABSTRACT]