ABSTRACT-The overexpression of ErbB-2 receptor relates to malignant transformation of breast cancer. The present study was carried out to establish the usefulness of a-tocopheryloxybutyric acid (TE) as a chemotherapeutic agent for human breast cancer. TE caused induction of apoptosis in MDA-MB-453 cells overexpressing the ErbB-2 receptor. TE reduced levels of activated ErbB-2 receptor and Akt. In contrast, TE induced the activation of p38, and SB203580, a specific inhibitor for p38, attenuated the TE-induced apoptosis. These data indicate that simultaneous occurrences of Akt inhibition and p38 activation by TE result in the cell death.Keywords: a-Tocopheryloxybutyric acid, Apoptosis, Breast cancer cell Overexpression of ErbB-2 receptor is seen in approximately 30% of human breast cancers, and the overexpression of the receptor is a negative prognostic factor following tumor resection and may be associated with increased resistance to cancer chemotherapy (1). A key mechanism by which the ErbB-2 receptor overexpression stimulates tumor cell growth and renders cells chemoresistant are as follows: survival signal transduction through the ErbB-2 receptor involves the phosphatidylinositol-3 kinase /Akt signaling pathway, and activated Akt is considered the focal point of a survival pathway known to protect cells from apoptosis by several stimuli (2). In a recent report, antisense oligonucleotide-dependent down-regulation of the ErbB-2 receptor in human breast cancer cells results in apoptotic cell death (3). Collectively, these reports encouraged us to develop a new therapeutic agent targeting the overexpressed ErbB-2 receptor in human breast cancer.Previous in vitro studies using a-tocopheryl succinate (TS) have shown that the antioxidative effect of a -tocopherol is not required for growth inhibition and apoptosis of several tumor cell lines including human breast cancer cells (4). In order to extrapolate this in vitro effect into an in vivo effect, we synthesized one a -tocopherol derivative, a-tocopheryloxybutyric acid (TE), which has no antioxidative effect in vivo (5). Since the ether bond in TE can not be hydrolyzed in vivo, this compound does not show any antioxidative effect (6). In fact, we demonstrated that TE was stable in vivo and inhibited cell proliferation during the carcinogenic process of lung tumorigenesis in mice (5, 7). In that study, we have suggested that TE stabilizes plasma membrane physicochemically and inhibits growth factor receptor-dependent mitogenic signaling, leading to suppression of the cell proliferation (5). Additionally, we found that TE suppressed the activation of epidermal growth factor receptor in a human lung cancer cell line through the stabilizing effect of TE on the plasma membrane (unpublished data). Overall, the stabilizing effect of TE may contribute to the suppression of ErbB-2 receptor activation in human breast cancer cells. In this context, the present study was carried out to clarify this possibility using a human breast cancer cell line, MDA-MB-453 overexpressing t...