ERK5 REGULATED BY ERBB-2 DRIVES PROLIFERATION OF TRIPLE NEGATIVE BREAST CANCER CELLS

CHERVO, MF; IZZO F; CHIAUZZI V; SCHILLACI R; MADERA S; QUINTA HR; CHARREAU EH; ELIZALDE PV; BEGUELIN W; VENTURUTTI, L; PROIETTI C. J; ROSALIA CORDO RUSSO

Congreso; LXI Reunión Anual de la SAIC; 2016

Triple negative breast cancer (TNBC) refers to the group oftumors with poor prognosis without clinically significant levels ofestrogen and progesterone receptors, and which lack membraneErbB-2 (MErbB-2) overexpression or gene amplification. Our hypothesisis that BC defined as TN indeed expresses ErbB-2 whichinstead of being localized at the membrane is present in the nucleuswhere it modulates tumor growth. We explored NErbB-2 presencein 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 explorethe biological function of NErbB-2, cells were transfected withErbB-2DNLS mutant which is unable to translocate to the nucleusand acts as dominant negative inhibitor of endogenous NErbB-2translocation. ErbB-2DNLS abolished NErbB-2 presence and proliferationin TNBC cell lines. Interestingly, we also demonstrated thatin vivo blockade of NErbB-2 expression suppresses tumor growth intwo pre-clinical models of TNBC. We previously perform a ChIP-Seqstudy to identify ErbB-2 binding sites in T47D cells treated with HRG,a ligand of ErbBs family. These cells express moderate amounts ofMErbB-2 and HRG treatment induces its nuclear migration. In thisChIP-Seq we identified Erk5 as a downstream target of NErbB-2.Here we explored Erk5 expression and function in TNBC. We foundthat protein and mRNA levels of Erk5 were increased in TNBC cells.Through ChIP assays using primers spanning the ErbB-2 bindingsite described in our ChIP-Seq, we observed a specific binding ofNErbB-2 to the Erk5 promoter in TNBC. Moreover we demonstratedthat blockade of Erk5 expression inhibits cell proliferation. Thisindicates that NErbB-2 may modulate Erk-5 expression, thus leadingto proliferation of TNBC. Our results identify NErbB-2 as a keyplayer in TNBC and highlight both NErbB-2 and Erk5 as potentialtherapeutic targets in these tumors.