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

SANTIAGO MADERA, MARÍA FLORENCIA CHERVO, LEANDRO VENTURUTTI, FRANCO IZZO, MARÍA ALICIA CORTES, VIOLETA CHIAUZZI, CECILIA PROIETTI, ROXANA SCHILLACI, ROSALÍA I. CORDO RUSSO, PATRICIA V. ELIZALDE

Congreso; LXI Reunión Anual de SAIC, 2016; 2016

Membrane overexpression of ErbB-2 (MErbB-2), member of the ErbB familyof receptor tyrosine kinases, or its gene amplification occurs in 15-20% ofbreast cancers (BC) and is associated with poor prognosis. ErbB-2 directedtherapies include the monoclonal antibody trastuzumab (Tz) and lapatinib (Lap),a tyrosine kinase inhibitor. Despite their clinical efficiency, many patientsdo not respond to such therapies and resistance to available drugs is still amajor clinical issue. Notably, ErbB-2 migrates to the nucleus (NErbB-2) whereit acts as a transcription factor (TF) or as a coactivator of TF. Here weexplored the role of NErbB-2 in BC resistant to Tz and Lap. For this purpose,we transfected BC cells with the ErbB-2∆NLS mutant which is unable totranslocate to the nucleus and also acts as a dominant negative inhibitor ofendogenous ErbB-2 nuclear translocation, and compare ErbB-2∆NLS, Tz and Lapeffects on MErbB-2-overexpressing human BC cells sensitive (BT-474) orresistant (JIMT-1) to Tz and Lap. Analysis of ErbB-2 subcellular distributionshowed that ErbB-2 was mainly located at the plasma membrane in BT-474 cellsand that heregulin (HRG), a ligand of ErbBs, induced NErbB-2 localization. InJIMT-1 resistant cells, NErbB-2 was constitutively detected and furtherenhanced by HRG. Nor Tz neither Lap blocked NErbB-2 presence in BT-474 andJIMT-1. Despite basal proliferation in BT-474 was inhibited by ErbB-2∆NLS, Tzand 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. We havepreviously demonstrated that NErbB-2 modulates BC growth acting as acoactivator of the TF Stat3 and regulating Cyclin D1 (CCND1) expression. Werevealed that HRG induces CCND1 expression and that only ErbB-2∆NLS inhibitsits levels in JIMT-1 cells. These findings highlight NErbB-2 as a noveltherapeutic strategy in Tz and Lap resistant BC, aiming the ErbB-2 oncogenicpathway unreached by current therapies.