Estrogen receptor (ER)3 gene expression in breast epithelium is an intricately regulated event. The human ER gene is transcribed from at least three different promoters which are expressed in a cell- and tissue-specific manner, and result in mRNA isoforms with unique 5'-untranslated exons. The ER is overexpressed in about two thirds of breast tumors, and even in early premalignant breast lesions compared with adjacent normal breast epithelium. Furthermore, normal breast epithelium as well as breast cancer tissue contains alternatively spliced ER mRNA variants where single or multiple exons are skipped. It is still unclear if any or all of the ER mRNA splicing variants are translated in vivo, and if a change in the balance of ER variants could effect tumor development and progression to hormone-independent growth. Although infrequent in primary breast cancer, single amino acid changes within the ER in metastatic disease which might influence cell proliferation may also contribute to neoplastic progression of the mammary epithelium.