Targeting ErbB-2 Nuclear Localization and Function Inhibits Breast Cancer Growth and Overcomes Trastuzumab Resistance

ROSALÍA CORDO RUSSO; WENDY BÉGUELIN; MARÍA DÍAZ FLAQUÉ; CECILIA PROIETTI; LEANDRO VENTURUTTI; NATALIA GALIGNIANA; MERCEDES TKACH; PABLO GUZMÁN; JUAN ROA; NEIL O'BRIEN; EDUARDO CHARREAU; ROXANA SCHILLACI; PATRICIA V ELIZALDE

ONCOGENE

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2014

0950-9232

Membrane overexpression of ErbB-2/HER2 receptor tyrosine kinase (MErbB-2) plays a critical role in breast cancer (BC). We and others demonstrated also the role of nuclear ErbB-2 (NErbB-2) in BC, whose presence we identified as a poor prognostic factor in MErbB-2-positive tumors. Current anti-ErbB-2 therapies, as with the antibody trastuzumab (Ttzm), target only MErbB-2. Here we found that blockade of NErbB-2 action abrogates growth of BC cells, sensitive and resistant to Ttzm, in a scenario in which ErbB-2, ErbB-3, and Akt are phosphorylated, and ErbB-2/ErbB-3 dimers are formed. Also, inhibition of NErbB-2 presence suppresses growth of a preclinical BC model resistant to Ttzm. We showed that at the cyclin D1 promoter, ErbB-2 assembles a transcriptional complex with Stat3 and ErbB-3, another member of the ErbBs family, which reveals the first nuclear function of ErbB-2/ErbB-3 dimer. We identified NErbB-2 as the major proliferation driver in Ttzm-resistant BC, and demonstrated that Ttzm inability to disrupt the Stat3/ErbB-2/ErbB-3 complex underlies its failure to inhibit growth. Furthermore, our results in the clinic revealed that nuclear interaction between ErbB-2 and Stat3 correlates with poor overall survival in primary breast tumors. Our findings challenge the paradigm of anti-ErbB-2 drug design and highlight NErbB-2 as a novel target to overcome Ttzm resistance.