Breast cancer cell estrogen receptor activity. Three general mechanisms of ERα signaling are depicted. First, ERα can bind estradiol (E2) and enter the nucleus, where it forms complexes with co-activators (CoAs) and regulates gene transcription by binding directly to estrogen response elements (EREs) specific to ERα or via interaction with other transcription factors (A). This genomic ERα activity can also be stimulated by Akt or MAPK-mediated phosphorylation of the receptor (B). Ligand-bound ERα can also remain outside the nucleus, where it complexes with the IGF-1R at the cell membrane or with other signaling molecules in the cytoplasm to activate the PI3K/Akt and MAPK pathways (C). IGF-1R crosstalk with the leptin receptor (OB-R) is also depicted (D). Each mechanism ultimately leads to the transcription of target genes that promote breast cancer cell growth. ERα, estrogen receptor alpha; IGF-1R, insulin-like growth factor 1 receptor.