Estrogen-Dependent Breast Cancer Signaling

Breast cancer is the second most common type of cancer worldwide. 95% of breast cancers are initially hormone dependent with estradiol playing an important role in disease development and progression. Eventually, tumors become hormone independent though this process may take several years. Estrogens are synthesized from androstenedione and testosterone which are converted to estrone and estradiol respectively by aromatase, a product of the CYP19A1 gene. Estrone is further converted to estradiol by the enzyme 17-βHSD. Hence deprivation of breast cancer cells of estrogens through inhibitors of aromatase is an important pharmacologic strategy used in treatment of patients.Biological action of estrogen is mainly mediated by genomic effects on transcription via binding of estrogen to either of its receptors - ER-α and ER-β. In the classical mode of action, receptors bind to estradiol, dimerize, translocate to the nucleus and transcriptionally regulate a number of genes by binding to EREs in promoter regions. Estradiol also acts via an ERE independent genomic path whereby it binds ER-α, translocates to the nucleus and binds other transcription regulators like c-Fos, c-Jun and Sp1. It is via this binding that it then indirectly controls the expression of genes like Cyclin D1 and IGF-1 that are important in cell cycle progression and cell growth.Non-genomic actions of estradiol are mediated by its binding to ER-α on or near the cell membrane. Ligand bound receptors rapidly activate signaling via PI3K/AKT, ERKs and STATs. ER interacts directly with the intracellular tyrosine kinase c-Src. However there is also positive cross talk between ER, c-Src, EGFR, and IGF-R in ER-positive breast cancer cells, resulting in the activation of Ras/Raf/ERK and STAT5 signaling pathways. Growth factor and steroid cross talk is an important means by which various biological functions are altered in tumor cells, especially in cancer cells that become tamoxifen-resistant.