TNFalpha Induces Resistance to Trastuzumab By Upregulation of Mucin 4 in HER2-Positive Breast Cancer

MERCOGLIANO MF; RIVAS MA; FRAHM I; ARES S; SCHILLACI R; DE MARTINO M; INURRIGARRO G; ALLEMAN DH; GERCOVICH FG; VENTURUTTI L; PROIETTI CJ; GIL DEZA E; ELIZALDE PV

Boston

Congreso; Endocrine Society?s 98th Annual Meeting and Expo; 2016

HER2 overexpression/amplification occurs in ~20% of invasive breast cancers and it is associated with poor prognosis. Trastuzumab (TZ), an antibody against HER2, has a response rate about 40-60% when used in combination with chemotherapy due to de novo or acquired resistance. Previously we have characterized tumor necrosis factor alpha (TNF) as a non-canonical activator of HER2. We demonstrated that stimulation of HER2-positive breast cancer cells with TNF induces in vitroHER2 transactivation, which in turn, activates NF-kB and induces cell proliferation even in the presence of TZ.The objective of this work was to study the role of TNF in de novo and acquired TZ resistance in HER2-positive breast cancer in vivo.For that purpose we generated tumor xenografts in nude mice from JIMT-1 and KPL-4 human cell lines, two de novo TZ-resistant models. When tumors were established, we administered 5 mg/kg TZ twice a week, 5 mg/kg etanercept (E, a TNF-blocking antibody) weekly or both simultaneously. Treatment with E or TZ did not affect tumor growth compared to IgG-treated animals. Remarkably, combined administration of TZ + E decreased tumor growth ~50% for JIMT-1 and ~70% for KPL-4 vs. IgG (p