Everolimus (
RAD001) is an inhibitor of
mammalian target of rapamycin used in combination with
exemestane to treat
hormone receptor-positive advanced
breast cancer. However, not all patients are equally sensitive to
RAD001 and certain patients develop resistance. Therefore, the present study analyzed the mechanisms involved in the resistance of
breast cancer cells to
RAD001 in order to identify a potential tool to overcome it. The effects of
RAD001 on the inhibition of cell viability, on the induction of apoptosis and autophagy and on the regulation of
survivin, an
anti-apoptotic protein, were evaluated in two
breast cancer cell lines: BT474 (
luminal B) and MCF7 (
luminal A).
RAD001 was demonstrated to induce autophagy in the two cell lines at following a short period of treatment (4 h) and to induce apoptosis exclusively in BT474 cells following longer periods of treatment (48 h).
RAD001 induced the downregulation of
survivin in BT474 cells and its upregulation in MCF7 cells. Consequently, inhibiting
survivin with
YM155 resulted in the acquired resistance of MCF7 cells to
RAD001 being reverted, restoring RAD001-induced apoptosis. These data demonstrated that
RAD001 exerted anti-proliferative and pro-apoptotic effects on
breast cancer cells, but that these effects were repressed by the simultaneous up-regulation of
survivin. Finally, the results demonstrated that inhibiting the expression of
survivin resulted in the restoration of the anti-neoplastic activity of
RAD001.