The PI3K/AKT/mTOR and the RAS/RAF/MEK/MAPK pathways. Phosphoinositide 3-kinase (PI3K) is a cytoplasmic lipid and protein kinase recruited to the membrane by activated growth factor receptors, including human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and insulin-like growth factor 1 (IGF-1R). PI3K phosphorylates the 3′-hydroxyl group of phosphoinositides to produce phoshatidylinositol-3,4,5-trisphosphate (PIP3), which is a second messenger that signals through AKT to activate several enzymes, kinases, and transcription factors, including mammalian target of rapamycin (mTOR). The RAS/RAF/MEK/MAPK pathway converges with the PI3K/AKT pathway and is now recognized as an alternative in mTOR activation. On the other hand, phosphatase and tensin homolog (PTEN) catalyzes PIP3 dephosphorylation, acting as a negative regulator of its activity. In parallel with activation of growth factor receptors, estrogens can activate nuclear estrogen receptors (ERs) (genomic pathway) or ERs on the membrane (non-genomic pathway). Membrane-associated ER binds to PI3K and activates molecules such as AKT and RAS, crosstalking with the growth factor signaling pathways. Erk1/2, extracellular-signal-regulated kinase 1/2; FOXO1, Forkhead box protein O1; MEK1/2, MAPK/Erk kinase 1/2; PIP, phosphatidylinositol phosphate; Raf, murine sarcoma viral oncogene homolog; Ras, rat sarcoma viral oncogene homolog; RHEB, Ras homolog enriched in brain; RTK, receptor tyrosine kinase; TSC1/2, tuberous sclerosis proteins 1 and 2.