Producción CyT
Congreso
Autoría
Maria Florencia Mercogliano
;
Mara De Martino
;
Leandro Venturutti
;
Martín Alfredo Rivas
;
Gloria Inurrigarro
;
Cecilia Jazmín Proietti
;
Isabel Frahm
;
Daniel Allemand
;
Ernesto Gil Deza
;
Sandra Ares
;
Felipe Gustavo Gercovich
;
Patricia V Elizalde
;
Roxana Schillaci
Fecha
2016
Editorial y Lugar de Edición
Endocrine Society
Resumen
Información suministrada por el agente en
SIGEVA
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, ...
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<0.01). To explore acquired resistance to TZ, we engineered the TZ-sensitive BT-474 human cell line to stably overexpress TNF (T2 cells). T2 xenografts were resistant to TZ administration but control tumors expressing empty vector (C) dramatically regressed under TZ treatment. Histopathological studies shed some light to understand the mechanism of TNF-induced TZ resistance revealing that T2 tumors showed mucinous foci. Indeed, in JIMT-1 cells it was reported that mucin 4 (MUC4) expression is able to mask the HER2 epitope recognized by TZ. Evaluation of MUC4 by immunohistochemistry (IHC) showed a more intense MUC4 staining in T2 than in C tumors, confirmed by WB. JIMT-1 and KPL-4 tumors treated with E and E + TZ showed weak to null staining for MUC4, in contrast to the strong staining obtained in IgG or TZ-treated tumors. Interestingly, T2 cells exhibited reduced binding of TZ, by immunofluorescence and flow cytometry, and reduced antibody-dependent cellular cytotoxicity compared to C2 cells, which was reversed by MUC4 silencing. In addition, p65 NF-kB knockdown, in T2 cells, impaired TNF-induced MUC4 expression. Furthermore we determined MUC4 by IHC in a cohort of 78 HER2-positive tumors and we obtained that MUC4 is an independent predictor of poor disease-free survival of patients treated with trastuzumab in the adjuvant setting (HR 5.4, CI 95%: 1.6-18.8, P=0.008).These results indicate that TNF is a source of TZ resistance stimulating MUC4 expression through activation of NF-kB pathway. Our data suggests that MUC4 could be used as a biomarker of resistance to TZ. In addition, blockage of TNF in combination with TZ could be a promising therapy in HER2-positive breast cancer patients to prevent or overcome TZ resistance.
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Palabras Clave
TNF alphaHER2BREAST CANCER