Nuclear ErbB-2’s role in the response to trastuzumab (TZ). BC cells sensitive to TZ show higher levels of MErbB-2 than those of NErbB-2. Their proliferation is stimulated by ErbB-2 signaling (e.g. PI3K/AKT) and nuclear (e.g. Stat3/ErbB-2/ErbB-3 transcriptional complex at cyclin D1 promoter) actions, both hierarchically equal. Inhibition of signaling with TZ or of nuclear action with hErbB-2ΔNLS inhibits proliferation. TZ-resistant cells show high levels of NErbB-2, which may be higher than those of MErbB-2. Nuclear ErbB-2 effect on proliferation is stronger than that of MErbB-2. Blockade of nuclear ErbB-2 effect with hErbB-2ΔNLS prevents BC growth in spite of the activation of signaling cascades.
