The mammalian target of rapamycin (mTOR), a downstream effector of the 
phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway 
that mediates cell survival and proliferation, is a prime strategic target for 
anticancer therapeutic development. By targeting mTOR, the immunosuppressant and 
antiproliferative agent rapamycin inhibits signals required for cell cycle 
progression, cell growth, and proliferation. Both rapamycin and novel rapamycin 
analogues with more favorable pharmaceutical properties, such as CCI-779, RAD 
001, and AP23573, are highly specific inhibitors of mTOR. In essence, these 
agents gain function by binding to the immunophilin FK506 binding protein 12 and 
the resultant complex inhibits the activity of mTOR. Because mTOR activates both 
the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation 
factor 4E-binding protein-1, rapamycin-like compounds block the actions of these 
downstream signaling elements, which results in cell cycle arrest in the G1 
phase. Rapamycin and its analogues also prevent cyclin-dependent kinase (CDK) 
activation, inhibit retinoblastoma protein phosphorylation, and accelerate the 
turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 
complexes, all of which potentially contribute to the prominent inhibitory 
effects of rapamycin at the G1/S boundary of the cell cycle. Rapamycin and 
rapamycin analogues have demonstrated impressive growth-inhibitory effects 
against a broad range of human cancers, including breast cancer, in preclinical 
and early clinical evaluations. In breast cancer cells, PI3K/Akt and mTOR 
pathways seem to be critical for the proliferative responses mediated by the 
epidermal growth factor receptor, the insulin growth factor receptor, and the 
estrogen receptor. Furthermore, these pathways may be constitutively activated 
in cancers with many types of aberrations, including those with loss of PTEN 
suppressor gene function. Therefore, the development of inhibitors of mTOR and 
related pathways is a rational therapeutic strategy for breast and other 
malignancies that possess a wide range of aberrant molecular constituents. This 
review will summarize the principal mechanisms of action of rapamycin and 
rapamycin derivatives, as well as the potential utility of these agents as 
anticancer therapeutic agents with an emphasis on breast cancer. The preliminary 
results of early clinical evaluations with rapamycin analogues and the unique 
developmental challenges that lie ahead will also be discussed.