The role of HER-2 oncoprotein in drug-sensitivity in breast cancer (review).

Overexpression of human epidermal growth factor receptor-2 (HER-2) oncoprotein is an important prognostic factor associated with a poor prognosis in breast cancer. Although treatment with trastuzumab, an anti-HER-2 antibody, increases drug-sensitivity in vitro and in vivo, the role of HER-2 oncoprotein in drug-sensitivity is still uncertain. The present work discusses the clinical significance of the HER-2 oncoprotein in drug-sensitivity in breast cancer based on previous clinical and basic results and reviews the current concept of HER-2 oncoprotein in drug-sensitivity. Introduction of HER-2 oncoprotein in vitro induces resistance to several anticancer drugs, including taxanes, cisplatin (CDDP) and 5-fluorouracil (5-FU) in breast cancer cells. The acquisition of drug-resistance by introduction of the HER-2 gene, however, depends on the cell type, because transfection of the HER-2 gene per se does not necessarily induce resistance to the same drugs in all types of breast cancer cells. In clinical studies, patients with HER-2 overexpression responded better to an anthracycline-based regimen than patients with low HER-2 expression, and their overall survival was also superior. In contrast, a correlation between the response to a cyclophosphamide + methotrexate + 5-FU regimen and overexpression of HER-2 is not certain. Taxanes responsiveness in patients with HER-2 oncoprotein overexpression was superior in patients with low HER-2 expression. Treatment with trastuzumab increased drug-sensitivity to anthracyclines, CDDP, and taxanes, but not to 5-FU, in breast cancer cells. Although the mechanism(s) by which trastuzumab enhances drug-sensitivity is not fully understood, modulation of the signal transduction pathways leading to apoptosis, such as down-regulation of the anti-apoptotic protein, Bcl-2, might be an important target to increase drug-sensitivity in breast cancer. HER-2 overexpression can be a good indicator for the selection of aniticancer drugs, especially for anthracycline containing regimens. To modulate HER-2-targeting therapy, the mechanism(s) by which trastuzumab enhances drug-sensitivity requires elucidation at the molecular level, including determination of other factors that influence drug-sensitivity, leading to a more promising treatment for individual patients receiving combination therapy with trastuzumab and anticancer drugs for breast cancer.