Etanercept as a New Agent for the Treatment of ErbB-2 Overexpressing Breast Tumors.

MARTÍN A. RIVAS, MERCEDES TKACH, ESTEBAN MARONNA, RICARDO SÁNCHEZ MARULL, WENDY BÉGUELIN, CECILIA J. PROIETTI, M. CELESTE DÍAZ FLAQUÉ, EDUARDO H. CHARREAU, PATRICIA V.. ELIZALDE, ROXANA SCHILLACI, ISABEL FRAHM

Congreso; 100th Annual Meeting of the United States and Canadian Academy of Pathology; 2011

Background: ErbB2 overexpressing breast cancer is associated with high aggressiveness and elevated metastatic potential. Patients with this diagnosis usually undergo treatment with the monoclonal antibody Herceptin. However, about 70% of patients develop primary or secondary resistance to Herceptin. We previously demonstrated that tumor necrosis factor alpha (TNF) induces proliferation of the BT-474 and SKBR-3 human breast cancer cell lines, through the transactivation of ErbB2. Moreover, we observed that TNF induces proliferation of these cell lines even in the presence of Herceptin. Design: In the present study we evaluated the expression of TNF in the Herceptin-resistant JIMT-1 human breast cancer cell line and the effectiveness of in vivo blockage of TNF with Etanercept, a TNF receptor 2-FcIgG fusion protein, on JIMT-1 tumor growth. Result: JIMT-1 cell line was grown in RPMI medium in the presence of 10%, 1% and 0.1% fetal calf serum and TNF expression was detected by Western blot. We observed that in all culture conditions JIMT-1 synthesize the pro-TNF protein of 26 kDa. As JIMT-1 is a cell line that overexpress ErbB-2 and show in vivo and in vitro resistance to Herceptin inhibitory effect, and taking into account that TNF is able to transactivate ErbB-2 and to promote growth of breast cancer cells, we asked whether TNF played a role in JIMT-1 growth in vivo. With that purpose we injected 3x106 JIMT-1 cells in NIH nude mice and when the tumors reached approximately 20mm3 (at day 9), we separated animals at random and started the treatment with Etanercept 5 mg/kg though ip injection twice a week or with human IgG as control (8 animals/group). Tumor growth was monitored along 24 days. We observed at day 35th that Etanarcept treatment inhibited 46% JIMT-1 tumor growth respect to IgG-treated animals (P<0.001). Histopathological analysis showed solid papilar, file tumor and G3, GN3 in both experimental groups. However IgG-injected animals showed tumors with no necrosis or fibrosis, while Etanercept-treated tumors exhibited 30-20% necrosis and 10% fibrosis. Moreover mitotic count per HPF was 7 and between 4-6 in IgG and Etanercept group respectively. Conclusion: As TNF has been shown to be present in the tumor microenvironment of a significant proportion of human infiltrating breast cancers, our findings would have clinical implication and propose Etanercept as a new agent to overcome clinically observed Herceptin resistance.