Mutations in the estrogen receptor gene.

Somatically generated mutations in the estrogen receptor (ER) have been found at the mRNA/cDNA level in human breast cancer biopsies and in established breast cancer cell lines. Aberrantly spliced ER mRNA causes the appearance of truncated or internally deleted ER protein forms. Studies on the functional activity of the ER variants in expression systems have revealed dominant-positive receptors that are transcriptionally active in the absence of estrogen, and dominant-negative receptors that are themselves transcriptionally inactive but that prevent the action of the normal receptor. The ER variants are believed to confer resistance to endocrine therapy in breast cancer patients. Abnormally spliced forms of ER, similar to those in breast cancer, have been reported in human meningiomas.