(a) 4-Hydroxytamoxifen (but not tamoxifen) up-regulates the expression of p27 in both estrogen receptor-positive and negative human breast cancer cells in vitro by down-regulating phosphorylation of 4E-BP1 and this down-regulation is mediated by upstream receptor tyrosine kinases/phosphoinositide 3-kinase/Akt/tuberous sclerosis complex proteins/mammalian target of rapamycin (RTKs/PI3K/Akt/TSC/mTOR) protein kinase signaling pathway (pathway #1 in Figures 5a, 5b and 7). The gene discussed is ESR1; the disease is breast carcinoma.