γ-Tocotrienol-induced disruption of lipid rafts in human breast cancer cells is associated with a reduction in exosome heregulin content.

Overexpression of heregulin, a potent ligand that activates HER3 and HER4 receptors, plays a significant role in the development of chemotherapy resistance in breast cancer patients. Exosomes released from cancer cells are small vesicles originating from the outward budding of lipid rafts that carry various mitogenic proteins that then act locally in an autocrine/paracrine manner to stimulate cancer cell growth. Since the anticancer activity of γ-tocotrienol has been shown to be mediated in part through the disruption of lipid rafts, studies were conducted to determine the effect of γ-tocotrienol on exosomes mitogenic biopotency. Exosomes isolated from the media of cultured T47D breast cancer cells were found to stimulate T47D cell growth in a dose-dependent manner. These growth stimulating effects were due to the high levels of heregulin contained in the exosomes that act to stimulate HER3 and HER4 activation, heterodimerization and mitogenic signaling. Exposure to 5 μM γ-tocotrienol resulted in the selective accumulation and disruption in the integrity of the lipid raft microdomain and a corresponding decrease in exosome heregulin content and mitogenic biopotency. These findings provide strong evidence indicating that the anticancer effects of γ-tocotrienol are mediated, at least in part, by directly disrupting HER dimerization and signaling within the lipid rafts and indirectly by reducing exosome heregulin content and subsequent autocrine/paracrine mitogenic stimulation.