Unraveling Nuclear ErbB-2 Role in Resistance to ErbB-2-targeted therapies in Breast Cancer.

MADERA S; CHERVO MF; VENTURUTTI L; IZZO F; CORTES MA; CHIAUZZI VA; PROIETTI CJ; SCHILLACI R; CORDO RUSSO R; ELIZALDE PV

Mar del Plata

Congreso; LXI Reunión Annual de SAIC (Soc. Arg. de Investigaciones Clínicas); 2016

SAIC

Membrane overexpression of ErbB-2 (MErbB-2), member of the ErbB family of receptor tyrosine kinases, or its gene amplification occurs in 15-20% of breast cancers (BC) and is associated with poor prognosis. ErbB-2 directed therapies include the monoclonal antibody trastuzumab (Tz) and lapatinib (Lap), a tyrosine kinase inhibitor. Despite their clinical efficiency, many patients do not respond to such therapies and resistance to available drugs is still a major clinical issue. ErbB-2 can translocate to the nucleus (NErbB-2) and act as a transcription factor (TF) or coactivator of TF. Here, we explored the role of NErbB-2 in BC growth and Tz/Lap resistance. For this purpose, we transfected BC cells with the ErbB-2∆NLS mutant which is unable to translocate to the nucleus and also acts as a dominant negative inhibitor of endogenous ErbB-2 nuclear translocation, and compare ErbB-2∆NLS, Tz and Lap effects on overexpressing-MErbB-2 human BC cells sensitive (BT-474) or resistant (JIMT-1) to Tz or Lap. Analysis of subcellular distribution showed that ErbB-2 was mainly located at the plasma membrane in BT-474 cells and that heregulin (HRG), a ligand of ErbBs, induced NErbB-2 localization. In JIMT-1 resistant cells, NErbB-2 was constitutively detected and further enhanced by HRG. Nor Tz neither Lap blocked NErbB-2 presence in BT-474 and JIMT-1. Despite basal proliferation rates in BT-474 were inhibited with ErbB-2∆NLS, Tz and Lap, only ErbB-2∆NLS was able to block HRG-induced proliferation. Moreover, ErbB-2∆NLS, but no Tz or Lap, inhibited JIMT-1 proliferation. Our recent findings demonstrated that NErbB-2 modulated BC growth acting as a coactivator of TF Stat3 and regulating Cyclin D1 (CCND1) expression. We revealed that HRG induced CCND1 expression and that only ErbB-2∆NLS inhibited its levels in JIMT-1 cells. These findings highlight NErbB-2 as a novel therapeutic strategy in Tz and Lap resistant BC, aiming the ErbB-2 oncogenic pathway unreached by current therapies.