TNFα acting on TNFR1 promotes breast cancer growth via p42/P44 MAPK, JNK, Akt and NF-κB-dependent pathways

Abstract Tumor necrosis factor α (TNFα) 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 TNFα, the participation of TNFα receptor (TNFR) 1 and TNFR2 and the molecular mechanism leading to breast cancer growth. We demonstrate that TNFα 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-κB) transcriptional activation. A TNFα-specific mutein selectively binding to TNFR1 induced p42/p44 MAPK, JNK, Akt activation, NF-κB transcriptional activation and cell proliferation, just like wild-type TNFα, 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 TNFα signaling and biological effect. Moreover, in vivo TNFα administration supported C4HD tumor growth. We also demonstrated, for the first time, that injection of a selective inhibitor of NF-κB activity, Bay 11-7082, resulted in regression of TNFα-promoted tumor. Bay 11-7082 blocked TNFα 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 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.