TNF-alpha acting on TNFR1 promotes breast cancer growth via p42/p44 MAPK, JNK, AKT and NF-Kappa B-dependent pathways

MARTÍN A RIVAS; ROMINA P CARNEVALE; CECILIA J PROIETTI; CINTHIA ROSEMBLIT; MARIANA SALATINO; EDUARDO H CHARREAU, PETER BROUCKAERT, PATRICIA V ELIZALDE, ROXANA SCHILLACI

EXPERIMENTAL CELL RESEARCH

ELSEVIER INC

Año: 2008 p. 509 - 529

0014-4827

Tumor necrosis factor α (TNFα) enhances proliferation of chemically-induced mammarytumors and of T47D human cell line through not fully understood pathways. Here, weexplored the intracellular signaling pathways triggered by TNFα, the participation of TNFαreceptor (TNFR) 1 and TNFR2 and the molecular mechanism leading to breast cancer growth.We demonstrate that TNFα-induced proliferation of C4HD murine mammary tumor cellsand of T47D cells through the activation of p42/p44 MAPK, JNK, PI3-K/Akt pathways andnuclear factor-kappaB (NF-κB) transcriptional activation. A TNFα-specific mutein selectivelybinding to TNFR1 induced p42/p44 MAPK, JNK, Akt activation, NF-κB transcriptionalactivation and cell proliferation, just like wild-type TNFα, while a mutein selective forTNFR2 induced only p42/p44MAPKactivation. Interestingly, blockage of TNFR1 or TNFR2 with specific antibodies was enough to impair TNFα signaling and biological effect. Moreover, invivo TNFα administration supported C4HD tumor growth. We also demonstrated, for the first time, that injection of a selective inhibitor ofNF-κB activity, Bay 11-7082, resulted in regressionof TNFα-promoted tumor. Bay 11-7082 blocked TNFα capacity to induce cell proliferation andup-regulation of cyclin D1 and of Bcl-xL in vivo and in vitro. Our results reveal evidence for TNFα as a breast tumor promoter, and provide novel data for a future therapeutic approach using TNFα antagonists and NF-κB pharmacological inhibitors in established breast cancer treatment.