RRR-alpha-tocopheryl succinate induces MDA-MB-435 and MCF-7 human breast cancer cells to undergo differentiation

RRR-alpha -Tocopheryl succinate (vitamin E succinate, VES) is a potent anti tumor agent, inducing DNA synthesis arrest, differentiation, and apoptosis. Because little is known about VES-Induced differentiation, studies reporte d here characterize VIES effects on the differentiation status of human bre ast cancer cell lines and investigate possible molecular mechanisms involve d. VES-induced differentiation of human MCF-7 and MDA-MB-435 breast cancer cells was characterized by morphological changes, induction of lipid drople ts, induction of beta -casein mRNA expression, and down-regulation of Her2/ neu protein. In contrast, VIES treatment of normal human mammary epithelial cells, MCF-10A cells, and T-47D cells did not induce differentiation. Stud ies addressing mechanisms showed that neither antibody neutralization of th e transforming growth factor-beta signaling pathway nor expression of a dom inant-negative mutant of c-Jun N-terminal kinase blocked the ability of VIE S to induce differentiation; however, treatment of cells with PD 98059, a c hemical inhibitor of mitogen-activated protein kinase kinase (MEK1/2), bloc ked the ability of VES to induce differentiation.