IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Erk5 regulated by ErbB-2 Drives Proliferation of Triple Negative Breast Cancer Cells
Autor/es:
BÉGUELIN W; DE MARTINO M; CHIAUZZI VA; SCHILLACI R; MADERA S; VENTURUTTI L; PROIETTI CJ; CORDO RUSSO RI; CHERVO MF; IZZO F; QUINTÁ HR; CHARREAU EH; ELIZALDE PV
Reunión:
Congreso; LXI Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica; 2016
Resumen:
Triple negative breast cancer (TNBC) refers to the group of tumors with poor prognosis without clinically significant levels of estrogen and progesterone receptors, and which lack membrane ErbB-2 (MErbB-2) overexpression or gene amplification. Our hypothesis is that BC defined as TN indeed expresses ErbB-2 which instead of being localized at the membrane is present in the nucleus where it modulates tumor growth. We explored NErbB-2 presence in TNBC using immunofluorescence (IF) and confocal microscopy. We found a strong NErbB-2 expression in a panel of TNBC cell lines (MDA-MB-468, HCC-70, MDA-MB-231 and MDA-MB453). To explore the biological function of NErbB-2, cells were transfected with ErbB-2DNLS mutant which is unable to translocate to the nucleus and acts as dominant negative inhibitor of endogenous NErbB-2 translocation. ErbB-2DNLS abolished NErbB-2 presence and proliferation in TNBC cell lines. Interestingly, we also demonstrated that in vivo blockade of NErbB-2 expression suppresses tumor growth in two pre-clinical models of TNBC. We previously perform a ChIP-Seq study to identify ErbB-2 binding sites in T47D cells treated with HRG, a ligand of ErbBs family. These cells express moderate amounts of MErbB-2 and HRG treatment induces its nuclear migration. In this ChIP-Seq we identified Erk5 as a downstream target of NErbB-2. Here we explored Erk5 expression and function in TNBC. We found that protein and mRNA levels of Erk5 were increased in TNBC cells. Through ChIP assays using primers spanning the ErbB-2 binding site described in our ChIP-Seq, we observed a specific binding of NErbB-2 to the Erk5 promoter in TNBC. Moreover we demonstrated that blockade of Erk5 expression inhibits cell proliferation. This indicates that NErbB-2 may modulate Erk-5 expression, thus leading to proliferation of TNBC. Our results identify NErbB-2 as a key player in TNBC and highlight both NErbB-2 and Erk5 as potential therapeutic targets in these tumors.