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

MERCOGLIANO, MARÍA FLORENCIA; DE MARTINO, MARA; VENTURUTTI, LEANDRO; RIVAS, MARTÍN A.; INURRIGARRO, GLORIA; PROIETTI, CECILIA J.; FRAHM, ISABEL; ALLEMAND, DANIEL; GIL DEZA, ERNESTO; ARES, SANDRA; GERCOVICH, FELIPE G.; ELIZALDE, PATRICIA V.; SCHILLACI, ROXANA

Boston

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

Endocrine Society

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 vitro HER2 transactivation, which in turn, activates NF-B 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