Breast cancer is one of the leading causes of cancer death among women in the world including Taiwan. Overexpression of ErbB-2, a receptor tyrosine kinase (RTK), has been detected in breast cancer and many other human tumors. In addition, elevated ErbB-2 expression is highly correlated with metastasis and poor clinical prognosis in breast cancer patients. Therefore, ErbB-2 has been used as a target for the development of novel cancer therapies. Intriguingly, emerging evidences show that many RTKs have repeatedly been found in the nucleus despite RTKs are traditionally known as transmembrane cell surface proteins. Recent study also shows that ErbB-2 is expressed in the nucleus in the primary human breast tumor tissues and human breast cancer cell lines. Nuclear ErbB-2 can bind to the promoter and transactivate transcription of cyclooxygenase-2 which has been known to be involved in tumor progression and metastasis, suggesting nuclear ErbB-2 may also contribute to the tumor malignancy. More recently, our studies have significant contribution to pioneer work in unraveling the novel mechanism by which ErbB-2, through endocytosis using endocytic vesicle as a vehicle, nuclear import receptor importin β1 as a driver and nuclear pore protein Nup358 as a traffic light, migrates from cell surface to the nucleus. This study also discovers that nuclear pore complex is involved in the nuclear translocation of ErbB-2. However, a refined and detailed view for how ErbB-2 traverses through the nuclear pore complex, and the biological significances and functions of the nuclear ErbB-2 are yet obscure. Hence, the following approaches are proposed to explore the functionality of nuclear ErbB-2 that has been overlooked in the past decades: (1) To elucidate the underlying mechanism by which ErbB-2 travels through the nuclear pore complex; (2) To identify novel nuclear target genes of nuclear ErbB-2 by systemic and unbiased genome-wide study; (3) To investigate the effects of nuclear ErbB-2 on tumor progression and metastasis.
